Next Article in Journal
Hexarelin Modulation of MAPK and PI3K/Akt Pathways in Neuro-2A Cells Inhibits Hydrogen Peroxide—Induced Apoptotic Toxicity
Next Article in Special Issue
Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues
Previous Article in Journal
Second-Generation Cephalosporins-Associated Drug-Induced Liver Disease: A Study in VigiBase with a Focus on the Elderly
Previous Article in Special Issue
Inhalation of Essential Oil from Mentha piperita Ameliorates PM10-Exposed Asthma by Targeting IL-6/JAK2/STAT3 Pathway Based on a Network Pharmacological Analysis

Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies

by 1,2,3 and 1,2,3,*
Center for Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
Leuven Cancer Institute (LKI), KU Leuven/UZ Leuven, Herestraat 49, 3000 Leuven, Belgium
Author to whom correspondence should be addressed.
Academic Editors: Bobin George Abraham and Anniina T. Virtanen
Pharmaceuticals 2021, 14(5), 443;
Received: 31 March 2021 / Revised: 3 May 2021 / Accepted: 4 May 2021 / Published: 8 May 2021
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)


The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in the activation of the JAK-STAT, PI3K-AKT and Ras-MAPK pathways, each contributing to survival, cell cycle progression, proliferation and differentiation. Here, we discuss the role of deregulated IL-7 signaling in lymphoid malignancies of B- and T-cell origin. Especially in T-cell leukemia, more specifically in T-cell acute lymphoblastic leukemia and T-cell prolymphocytic leukemia, a high frequency of mutations in components of the IL-7 signaling pathway are found, including alterations in IL7R, IL2RG, JAK1, JAK3, STAT5B, PTPN2, PTPRC and DNM2 genes.
Keywords: interleukin-7; cytokine receptor; JAK kinases; signaling; lymphocyte development; lymphoid malignancy; acute lymphoblastic leukemia; kinase inhibitor; targeted treatment interleukin-7; cytokine receptor; JAK kinases; signaling; lymphocyte development; lymphoid malignancy; acute lymphoblastic leukemia; kinase inhibitor; targeted treatment

1. The Role of IL-7 Signaling in Lymphocyte Development

Interleukin-7 (IL-7) is crucial for lymphocyte development, as well as for the survival, proliferation, differentiation and activity of mature T- and B-cells [1]. The IL-7 receptor (IL-7R) is a heterodimer consisting of the specific IL-7Ralpha chain (IL-7Rα, CD127; encoded by the IL7R gene) and the common gamma chain (γc, CD132; encoded by the IL2RG gene), which is shared by receptors for IL-2, IL-4, IL-9, IL-15 and IL-21. Whereas IL-7Rα expression is tightly regulated and almost exclusively found on lymphoid cells, γc is constitutively expressed by most hematopoietic cell types [1,2]. Mice with IL-7 or IL-7Rα deficiency show a block in T- and B-lymphocyte development, resulting in non-functional peripheral T-cells and reduced numbers of functional peripheral B-cells [3,4,5]. In humans, genetic alterations causing the loss-of-function of IL-7Rα or γc result in severe combined immunodeficiency through impaired thymocyte differentiation and T-cell survival, emphasizing the critical role of IL-7 signaling in T-cell development [6,7,8].
IL-7 is produced by stromal cells in lymphoid organs such as the bone marrow, thymus, spleen and lymph nodes, as well as in non-lymphoid tissues including the intestine, skin, lung and liver [9,10]. In contrast to other cytokines, the production of IL-7 occurs at a fixed rate, uninfluenced by external stimuli. The amount of available IL-7 is therefore dependent on the rate of consumption by lymphocytes rather than on the rate of production and, as such, plays a role in regulating lymphocyte homeostasis. In normal conditions, the amount of IL-7 is just sufficient to support the survival of a specific number of T-cells, with excess T-cells not being able to survive. After lymphocyte depletion, however, abundant IL-7 will stimulate lymphocyte proliferation until homeostasis is restored [1,11]. Contrary to the constitutive production of IL-7, the expression of IL7R is tightly regulated during lymphocyte development and, in mature T-cells, extremely influenced by external stimuli [1,12,13].
IL-7 signaling is initiated when binding of IL-7 to the IL-7R induces the heterodimerization of and conformational changes in IL-7Rα and γc (Figure 1). These conformational changes bring together the tyrosine kinases Janus kinase 1 (JAK1), associated with IL-7Rα, and JAK3, associated with γc, which phosphorylate each other, thereby increasing their kinase activity. Subsequently, the activated JAK proteins phosphorylate tyrosine residue Y449 in the cytoplasmic domain of IL-7Rα and, as such, create a docking site for Src homology-2 (SH2) domain-containing downstream effectors. One such critical effector is signal transducer and activator of transcription 5 (STAT5), which is phosphorylated on tyrosine residue Y694 by the JAK proteins upon docking to IL-7Rα. Phosphorylated STAT5 then homodimerizes and translocates to the nucleus, where it activates the expression of its target genes, such as BCL2, CISH, MYC, OSM and PIM1, which are involved in inhibiting apoptosis, as well as stimulating survival, cell cycle progression, proliferation and differentiation [1,14,15,16,17]. STAT5 is also phosphorylated on serine residues S725 and S779 by serine/threonine kinases, and this phosphorylation is required for full transcriptional activation of STAT5 [18]. Other effector molecules downstream of IL-7 signaling include STAT1 and STAT3, which play a role in, amongst others, T-cell homeostasis [19,20,21,22]. In addition to the JAK-STAT pathway, IL-7 signaling activates the PI3K-AKT and Ras-MAPK pathways [23,24]. While PI3K-AKT activation is initiated by the docking of PI3K to phospho-Y449, Ras-MAPK signaling is suggested to be activated via a cross-talk with the JAK-STAT pathway [10,25,26,27,28,29].
Physiologically, IL-7-initiated signaling is only transient, as negative regulation and termination of the signal is rapidly activated by (1) clathrin-dependent endocytosis and the subsequent proteasomal degradation of IL-7Rα, (2) dephosphorylation of JAK1, JAK3 and STAT5 by the protein tyrosine phosphatases (PTP) non-receptor type 2 (PTPN2) and receptor type C (PTPRC, also known as CD45), (3) the suppression of IL-7 signaling by the suppression of cytokine signaling (SOCS) proteins, and (4) the SUMOylation of STAT5 by protein inhibitors of STATs (PIAS) proteins [30,31].
In addition to its role in IL-7 signaling, IL-7Rα can heterodimerize with cytokine receptor-like factor 2 (CRLF2, also known as TSLPR), thereby forming the receptor for thymic stromal lymphopoietin (TSLP) [32,33]. The inclusion of IL-7Rα in both the IL-7 and TSLP receptor complex suggests that the ligand-driven dimerization of these two different receptors results in the activation of a common downstream signaling pathway. Indeed, signaling induced by both receptors activates STAT5 and upregulates the expression of STAT5 target genes [34]. However, the mechanisms underlying the transcriptional activation of STAT5 differ [35]. Whereas IL-7 signaling activates STAT5 via the phosphorylation of JAK1 and JAK3, TSLP-initiated signaling does so by the activation of JAK1 and JAK2 (Figure 2) [22,36].
In contrast to mouse Tslp signaling which promotes the proliferation and differentiation of pre-B-cells, peripheral CD4+ T-cells and myeloid dendritic cells (mDCs), in humans, TSLP only activates mDCs [37,38,39,40,41,42,43]. As such, via interaction between these activated mDCs and CD4+ T-lymphocytes, TSLP-initiated signaling is involved in the regulation of the positive selection of regulatory T-cells, maintenance of peripheral CD4+ T-cell homeostasis and induction of CD4+ T-cell-mediated allergic inflammation [43,44,45,46,47]. However, although in vitro and in vivo experiments suggest that TSLP may play a role in lymphocyte development, studies in mice and humans lacking the ability to respond to TSLP show that TLSP signaling is not essential for lymphopoiesis [6,48,49].

2. The Role of IL-7 Signaling in Acute Lymphoblastic Leukemia

The role of IL-7-induced signaling in the development of lymphoid malignancies has been suggested by several mouse models. IL-7 transgenic mice displayed accelerated mortality due to T- and B-cell lymphoma development and also AKR/J mice, which overexpress wild type IL-7Rα, spontaneously developed T-cell lymphoma [50,51,52,53]. Moreover, it was demonstrated in patient-derived xenograft (PDX) models that T-cell acute lymphoblastic leukemia (T-ALL) cells developed more slowly when engrafted in IL-7-deficient mice compared to mice expressing IL-7. In these models, IL-7 deficiency resulted in a decreased expansion of T-ALL cells in the bone marrow, reduced infiltration in the peripheral blood and extramedullary sites and delayed leukemia-associated death [54].
In addition, wild type IL-7Rα is detected on leukemic cells from more than 70% of patients with ALL, and these IL-7Rα cell surface expression levels correlated with IL-7 response in vitro [2,50,53,54,55,56]. Moreover, several studies have identified oncogenic mechanisms that increase IL-7Rα expression and cell surface levels [57]. For example, the transcription factor NOTCH1, which is activated by gain-of-function mutations in more than 65% of T-ALL, upregulates the expression of IL7R [58]. In early T-cell precursor ALL (ETP-ALL), the aberrant expression of the transcription factor ZEB2 resulted in increased expression of IL7R, and ZEB2-induced IL7R upregulation promoted T-ALL cell survival in vitro and in vivo [59]. Furthermore, the arginine to serine substitution at residue 98 (R98S) of RPL10, a mutation identified in up to 8% of patients with T-ALL, was shown to increase the expression of IL7R and downstream signaling molecules [60]. Lastly, the reduced expression of SOCS5 was found in T-ALL patients with KMT2A translocations and resulted in the upregulation of IL-7Rα expression levels and the activation of JAK-STAT signaling, thereby promoting T-ALL cell proliferation in vitro and in vivo [61].
These results already show that the deregulated expression of both IL-7 and its receptor can contribute to the development of lymphoid malignancies, as well as that T-ALL cells often remain dependent on IL-7-induced signaling for survival, cell cycle progression and proliferation. Moreover, in the last few years, it has become increasingly clear that in lymphoid malignancies, many signaling molecules of the IL-7 pathway carry genetic alterations. Below, we discuss the role of the deregulation of the most important components of IL-7 signaling in lymphoid malignancies (Figure 3).

2.1. Mutations in the IL-7 Receptor

IL-7Rα is a type I transmembrane cytokine receptor consisting of an extracellular domain, a single transmembrane domain and an intracellular domain [62]. The extracellular domain contains two fibronectin type III-like domains (DN1 and DN2) with four paired cysteines and a juxtamembrane WSxWS motif which are involved in mediating the correct folding of the extracellular domain and, as such, binding of IL-7 to the IL-7R [63]. The intracellular region consists of a four-point-one protein, ezrin, radixin, moesin (FERM) domain, comprising a juxtamembrane BOX1 domain that is required for association with JAK1, as well as the tyrosine residue Y449 which, when phosphorylated, creates a docking site for STAT5 (Figure 3) [64].
Gain-of-function mutations in IL-7Rα are identified in up to 10% of T-ALL and about 2–3% of B-cell precursor ALL (B-ALL) cases [65,66,67,68,69,70]. In T-ALL, IL7R mutations are substantially enriched in immature T-ALL cases and in cases aberrantly expressing TLX1, TLX3 or HOXA, and also in B-ALL IL7R alterations are found in specific subtypes, including Ph-like, CRLF2-rearranged, iAMP21-positive, IKZF1 mutant or PAX5 mutant B-ALL [57]. The IL7R mutations are heterozygous and almost always located in exon 6, where they introduce in-frame insertions or deletions–insertions in the extracellular juxtamembrane (EJ) or transmembrane (TM) domain of IL-7Rα. Strikingly, the majority of these alterations (>80%) introduce an unpaired cysteine (Figure 3) [64].
Several studies investigating the underlying mechanism of cysteine-introducing mutations have shown that the unpaired cysteine promotes the formation of de novo intermolecular disulfide bonds between mutant IL-7Rα chains resulting in constitutive IL-7Rα homodimerization and JAK1 and STAT5 phosphorylation, independent of IL-7, γc or JAK3 [24,65,66,67]. The expression of cysteine-introducing mutations in both the IL-7-dependent thymocyte cell line D1 and the IL-3-dependent pro-B cell line Ba/F3 was able to transform cells to cytokine-independent proliferation. Transformed cells were sensitive to the JAK inhibitors Pyridone 6, ruxolitinib and tofacitinib, as well as a STAT5-specific small molecule inhibitor [24,65,67,71]. Moreover, the intravenous injection of IL-7Rα p.L242-L243insNPC-expressing D1 cells, as well as IL-7Rα p.L242-L243insGC- and IL-7Rα p.IL241–242TC-positive Arf-/- thymocytes into Rag-/- mice resulted in leukemia development. Treatment with ruxolitinib in these models significantly reduced leukemic burden and prolonged survival [71,72]. These observations imply that cysteine-introducing mutations in IL-7Rα drive cellular transformation in vitro and leukemia development in vivo by activating downstream JAK-STAT signaling.
In addition to these insertions or deletion–insertions, there is also the recurrent point mutation IL-7Rα p.S185C that results in the introduction of an unpaired cysteine residue [66]. This mutation is exclusively identified in B-ALL and conferred IL-3-independent proliferation on Ba/F3 cells only upon co-expression with CRLF2 [66].
The non-cysteine IL7R mutations can be classified into two groups according to their localization in the EJ-TM or transmembrane region (TM) [64]. However, the exact mechanisms by which these non-cysteine mutations contribute to increased IL-7R signaling are not fully resolved yet. EJ-TM mutations, constituting 4% of IL7R mutations, mainly introduce a positively charged amino acid (i.e., arginine, histidine or lysine) in IL-7Rα, which can engage in electrostatic interactions with a negatively charged residue present in wild type γc [24,73]. These alterations are thus suggested to facilitate IL-7Rα-γc heterodimerization and increase IL-7 sensitivity. On the other hand, TM mutations (9%) insert residues which generate de novo homodimerization motifs (such as ExxxV, SxxxA and SxxxG) which are suggested to form intermolecular hydrogen bonds, thereby stabilizing IL-7Rα homodimers and inducing IL-7-independent signaling [74,75,76].
These results illustrate that there are different mechanisms by which activating IL-7Rα mutations contribute to the increased activation of the IL-7 signaling pathway and that a variety of oncogenic effects can be expected, ranging from a slight increase in IL-7 sensitivity to constitutive IL-7-independent signaling. Moreover, as IL-7 is only available at limited amounts in the thymus and in other lymphoid tissues, leukemia cells that become increasingly sensitive to IL-7 have a survival and proliferative advantage compared with wild type lymphoid cells as a result of increased IL-7 signaling pathway activation, most likely explaining why in many T-ALL cases that carry a mutation in IL7R, additional alterations in JAK1, JAK3, PTPN2, PTPRC and/or DNM2 are found, as described in the following sections. By accumulating multiple mutations in the IL-7 signaling pathway, cells eventually become (almost) completely independent of IL-7.
In contrast to IL-7Rα, which is recurrently mutated in ALL as described above, activating alterations in the other IL-7 receptor chain, γc (Figure 1) are extremely rare. In fact, no such alterations have been described in ALL, but some were identified in T-cell prolymphocytic leukemia (T-PLL), a rare T-cell leukemia [77]. Although rare, these mutations further illustrate the importance of deregulated IL-7 signaling in various lymphoid malignancies and are in line with the major role for IL-7 in regulating T-cell survival and proliferation.

2.2. Mutations in the JAK1 and JAK3 Tyrosine Kinases

The Janus kinase (JAK) family comprises four members of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) which associate with cytokine receptors that lack intrinsic kinase activity to mediate cytokine-induced signaling. All JAK family members share a common structure consisting of an N-terminal FERM domain and SH2-like domain which are required for associating the JAK proteins to cytokine receptors, a C-terminal pseudokinase (JAK homology 2, JH2) and kinase domain (JH1) [78,79]. The catalytically inactive JH2 pseudokinase domain functions as a negative regulator of the JH1 kinase domain, as it stabilizes JH1 in an inactive conformation in the absence of cytokines (Figure 3) [80,81,82]. In contrast to their conserved structure, the different JAK family members preferentially associate with specific cytokine receptors that are expressed by specific cell types and, as such, facilitate difference in function [83]. At the IL-7R, JAK1 associates with IL-7Rα, whereas JAK3 binds to γc (Figure 1).
Mutations in JAK1 and JAK3 are most frequent in T-ALL and T-PLL and are mainly found in the JH2 pseudokinase and JH1 kinase domains (Figure 3) [67,83,84,85,86,87,88,89,90,91,92]. The prevalence of JAK1 and JAK3 mutations differs substantially between studies, dependent on the number and age of the patients included [67,83,84,85,86,87,88,90,91,92,93]. JAK3 is the most frequently mutated component of the IL-7 signaling pathway, with mutations identified in up to 16% of T-ALL, while JAK1 alterations are rather rare and mainly found in cases that also carry JAK3 or IL7R mutations. Moreover, if activating JAK1 mutations do occur, they are usually found in subclones, rather than in the major clone. It is surprising that JAK1 is less frequently mutated than JAK3, since previous studies demonstrated that JAK1 is the most important kinase of the IL-7 signaling pathway [94]. This could suggest that extremely strong activation of the IL-7 signaling pathway is not preferred, as it could result in cell exhaustion and/or other undesirable side effects.
The transforming capacity of JAK3 mutations has been investigated using in vitro cell-based assays and in vivo bone marrow transplant models [84,94,95,96]. Although the majority of JAK3 mutations in ALL are located in the JH2 pseudokinase and JH1 kinase domain, the most frequent alteration, JAK3 p.M511I, affects an amino acid right outside the pseudokinase domain [67,89,90,97]. Moreover, not all mutations identified are gain-of-function alterations that drive leukemogenesis. So-called passenger mutations, such as some JAK3 kinase domain mutations and the majority of mutations in the FERM/SH2 domain of JAK3, do not contribute to cellular transformation nor leukemia development [84,94,95,96].
Reconstitution of the IL-7R in HEK293T cells showed that the JAK3 pseudokinase domain mutants required a functional receptor complex consisting of IL-7Rα and γc to constitutively phosphorylate and activate STAT5 [94,95]. In contrast, this was not the case for the JAK3 kinase domain mutants p.L857P and p.L857Q. In line with these observations, it was demonstrated that JAK3 pseudokinase mutations signal through JAK1 and that JAK1 kinase activity is required for their oncogenic properties [94]. These differences in functional IL-7R requirement and downstream JAK kinase activity are important to determine which JAK inhibitors can be used to target leukemia cells carrying a certain JAK3 mutation. Ruxolitinib, which is a JAK1/JAK2-selective inhibitor, inhibited the proliferation of cells transformed by pseudokinase domain JAK3 mutants, whereas cells expressing JAK3 kinase domain mutations were less sensitive [94,95]. The latter were, in contrast, more sensitive to JAK3-specific inhibitors [84,95,96]. For the JAK1/JAK3-specific inhibitor tofacitinib, the pseudokinase and kinase domain mutants showed a similar sensitivity, whereas treatment with a combination of ruxolitinib and tofacitinib synergistically inhibited the proliferation of cells transformed by pseudokinase, but not kinase domain mutants [94,95].
Mouse bone marrow transplant models of different JAK3 mutants resulted in the development of lymphoid malignancies with an average disease latency of about 150 days [94]. Interestingly, these lymphoid malignancies showed slight differences in phenotype. That is, while pseudokinase domain mutants homogenously induced a T-ALL-like disease, the expression of kinase domain mutations resulted in more heterogenous phenotypes with various lympho- and myeloproliferative malignancies [94]. In addition, a recent study by de Bock and colleagues showed that co-expression of the JAK3 mutant p.M511I and HOXA9 substantially reduced disease latency to about 40 days as a result of strong oncogenic cooperation [98].
In up to a third of T-ALL patients carrying a JAK3 mutation, mutant JAK3 signaling is further enhanced by either the loss of wild type JAK3 or the acquisition of a secondary JAK3 mutation [99]. Degryse et al. showed that wild type JAK3 competed with JAK3 pseudokinase domain mutants for binding to the IL-7R and, as such, suppressed its transforming capacity. Moreover, acquiring a second mutation in the mutant JAK3 allele increased downstream JAK-STAT signaling, as shown by increased STAT5 phosphorylation.
The most extensively studied genetic alterations in JAK1 are the pseudokinase domain mutations p.A634D, p.V658F and p.S646F [56,81,82,83,85,87,100]. These three mutants, as well as all other pseudokinase and kinase domain mutants studied, were able to transform Ba/F3 cells to IL-3-independent proliferation by constitutively phosphorylating STAT5. In the BM5247 T-lymphoma cell line, the expression of JAK1A634D resulted in strong JAK1 and STAT5 phosphorylation and, as such, protection from dexamethasone-induced apoptosis [83]. Moreover, the three JAK1 pseudokinase mutants p.A634D, p.V658F and p.S646F were able to constitutively phosphorylate and activate STAT proteins when expressed in HEK293T and/or U4C cells in the absence of any other receptor complex component [81,82,83,87]. Hornakova et al., however, showed that the recruitment and docking of both JAK1 and STAT5 to a functional alpha chain were required for the alpha chain-mediated constitutive activation of STAT proteins by JAK1 pseudokinase domain mutants [82,100].
The proliferation of JAK1S646F-transformed Ba/F3 cells was inhibited by ruxolitinib and also a PDX model of JAK1 mutant B-ALL showed sensitivity to ruxolitinib [56,85,87]. Overall, these results together with the results on IL-7Rα and JAK3 indicate that ruxolitinib, which is currently used to treat JAK2 mutant malignancies, may also be a promising drug for the treatment of IL7R, JAK1 or JAK3 mutant cases.

2.3. Mutation in the STAT Family Member STAT5B

Signal transducer and activator of transcription 5B (STAT5B) belongs to the STAT family of transcription factors, which play a critical role in cytokine receptor signaling. All STAT family members have a common structure. The N-terminal domain is required for interaction with co-activators as well as higher-order interactions between activated STAT5 dimers. The central DNA-binding domain, which is involved in the recognition of the specific DNA binding sequence, is coupled to the SH2 domain by a flexible linker. This SH2 domain recognizes phosphotyrosine residues and plays a critical role in the recruitment of STATs to activated cytokine receptors, the interaction of STAT family members with JAK proteins and the dimerization of phosphorylated STAT proteins. Between the SH2 domain and the transactivation domain resides a conserved tyrosine residue (Y694) whose phosphorylation is essential for the activation and dimerization of all STAT family members. The C-terminal transactivation domain is required for coordinating the transcriptional machinery and contains two serine residues whose phosphorylation is required for full transcriptional activity (Figure 3) [101].
Gain-of-function alterations in STAT5B are identified in 6% of pediatric and up to 9% of adult T-ALL and are located in both the SH2 and transactivation domain. The most prevalent STAT5 alteration is the p.N642H SH2 domain mutation (Figure 3) [102,103]. In T-PLL, a similar distribution of STAT5B mutations is observed [77].
In vitro and ex vivo cell-based assays showed that SH2 domain mutations and, to a lesser extent, transactivation domain mutations resulted in increased STAT5B Y694 phosphorylation and the upregulation of STAT5 target genes [77,102,103]. Moreover, the expression of STAT5BN642H was able to transform cells to cytokine-independent proliferation [77,103].
Interestingly, Ba/F3 cells transformed by the expression of STAT5BN642H showed sensitivity to ruxolitinib and tofacitinib, and treatment with these JAK inhibitors resulted in decreased STAT5B phosphorylation and reduced STAT5B target gene expression [104]. These in vitro observations imply that STAT5BN642H induces JAK kinase activity, and that this activation is required for the phosphorylation and transcriptional activation of STAT5B. Indeed, also in vivo experiments using a STAT5BN642H transgenic mouse model illustrated that the transforming capacity of STAT5BN642H depends on phosphorylation by JAK1, as the leukemic burden was substantially reduced upon treatment with ruxolitinib [105]. In contrast, Kontro and colleagues observed that leukemic cells of a T-ALL patient carrying three STAT5B mutations did not show sensitivity to ruxolitinib or tofacitinib when treated ex vivo, suggesting that the co-occurrence of these three mutations constitutively activated STAT5B, independent of upstream JAK kinase activity [102].

2.4. Inactivation of the Protein Tyrosine Phosphatases PTPN2 and CD45

Protein phosphatases can be classified into two major families based on their substrate specificity: the protein tyrosine phosphatases (PTPs) and the serine/threonine phosphatases. The 107 human PTP genes are subdivided into four classes (Class I–IV) based on the amino acid sequence in the catalytic domain. Class I is the largest and can be classified into classical PTPs and dual specificity PTPs, and the former can be further subdivided into receptor PTPs and non-receptor PTPs. Both Class I and Class II PTPs have been shown to negatively regulate and terminate JAK-STAT signaling by dephosphorylating both JAK and STAT molecules [106].
PTP non-receptor type 2 or PTPN2 (also known as TC-PTP) is a ubiquitously expressed non-receptor PTP that exists as two splice variants [107]. Both variants consist of an N-terminal catalytic PTP domain followed by a C-terminal domain which includes either a nuclear localization signal or an ER targeting sequence (Figure 3) [106]. Although PTPN2 deficiency increases JAK-STAT signaling in various cell types, loss-of-function genetic alterations in PTPN2 have been identified mainly in TLX1-expressing T-ALL cases [107,108]. These loss-of-function alterations typically involve mono- or bi-allelic deletions of the entire PTPN2 gene [107].
The mechanism by which PTPN2 deletion contributes to T-ALL is assigned to the negative regulation of JAK-STAT signaling [107,108,109]. In T-ALL, the expression of TLX1 is typically associated with gain-of-function mutations in the IL-7 signaling pathway, as well as with ABL1 fusion proteins, which both result in the constitutive activation of STAT5. Kleppe et al. found a direct cooperation between the loss of PTPN2 and oncogenic kinases involved in IL-7R-JAK-STAT signaling, such as mutant JAK1 and the NUP214-ABL1 fusion protein [107,109].
Another negative regulator of IL-7 signaling is the PTP receptor type C (PTPRC, also known as CD45) which is a classical receptor PTP that exists as several splice variants that are variably expressed by the majority of hematopoietic cells [110]. CD45 is a critical positive regulator of T- and B-cell receptor-mediated signaling [111,112,113], as well as a negative regulator of members of the JAK family via direct dephosphorylation or by adaptor protein recruitment [114,115]. The loss of CD45 expression has been observed in up to 4% of pediatric T-ALL and around 13% of pediatric B-ALL [116]. Moreover, Porcu et al. identified CD45 inactivating alterations in patients with T-ALL, resulting in low CD45 expression or the loss of CD45 phosphatase activity [117]. Interestingly, these CD45 mutations all co-occurred with activating mutations in the IL-7R-JAK-STAT pathway and CD45 knockdown experiments showed the increased activation of JAK-STAT signaling downstream of mutant IL-7Rα or JAK1 [117].

2.5. Alterations in DNM2

Dynamin 2 (DNM2), a ubiquitously expressed large GTPase, plays an essential role in clathrin-dependent endocytosis (CDE), a process that regulates receptor signaling as well as the recycling and degradation of receptor molecules [118]. During CDE, ligand-bound receptors, such as IL-7-bound IL-7R, are recruited to clathrin-coated pits in the cell membrane which then invaginate to form budding vesicles. Subsequently, GTP-dependent constriction by DNM2 results in the formation of clathrin-coated endocytic vesicles [118]. DNM2 contains five distinct domains, including the N-terminal GTPase domain and the C-terminal GTPase effector domain, that each impart a specific function during CDE (Figure 3) [119].
Genetic alterations in DNM2 are identified in around 10% of adult T-ALL and up to 20% of the ETP subtype of T-ALL and are heterozygous, with frameshifts, non-sense, missense and splice mutations and deletions throughout the whole gene [67,120].
The mechanism by which alterations in DNM2 promote leukemogenesis was elucidated by Tremblay and colleagues using a Lmo2TgDnm2V265G transgenic mouse model [118]. They observed that this mutation in Dnm2 cooperated with Lmo2 expression to accelerate the development of T-ALL. DNM2 loss-of-function impaired the formation of clathrin-coated endocytic vesicles and blocked the internalization of IL-7R, which led to enhanced IL-7 signaling in preleukemic thymocytes. In agreement with this, DNM2 mutations co-occur with additional activating alterations in the IL-7 signaling pathway, suggesting a cooperation between these genetic alterations in leukemia development [67,108].

2.6. Alterations in the CRLF2 Receptor Chain

As described above, IL-7Rα can also form heterodimers with CRLF2 (Figure 2), a type I transmembrane cytokine receptor with a unique conformation and only one single tyrosine residue at the C-terminus (Figure 3) [35]. This heterodimer forms the receptor for TSLP.
Gain-of-function alterations in CRLF2 are identified in about 5% of pediatric and adult B-ALL overall and in up to 60% of B-ALL arising in patients with Down syndrome, but so far not in any other lymphoid malignancy [121,122,123,124,125]. The most common genetic abnormalities involving CRLF2 result in its upregulation due to chromosomal rearrangements at the pseudoautosomal region 1 (PAR1) of chromosome X or Y or translocations of the CRLF2-containing PAR1 with the [email protected] locus [121,123,124,125].
The overexpression of CRLF2 was able to enhance the proliferation of early B-cell precursor cells in vitro [121]. However, CRLF2 knockdown in the B-ALL cell line MUTZ5 only partially abrogated cell proliferation and CRLF2 expression in primary bone marrow progenitor cells did not result in leukemia development in vivo [121,126]. Together, these observations imply that the aberrant expression of CRLF2 is not sufficient to drive malignant transformation. Indeed, in the majority of CRLF2-overexpressing ALL patients, additional mutations in the TSLP signaling pathway are identified. For example, around half of ALL patients overexpressing CLRF2 carry gain-of-function mutations in JAK2 [126,127], indicating that these two genetic alterations may cooperate to promote leukemogenesis [125].
An activating mutation in CRLF2, which results in the substitution of the phenylalanine residue F232 to an unpaired cysteine, has also been identified in CRLF2-overexpressing B-ALL (Figure 3) [123,124]. Similar to the cysteine-introducing alterations in IL7R, the unpaired cysteine residue is introduced in the EJ-TM region and promotes the formation of de novo intermolecular disulfide bonds between mutant chains [123]. As such, this p.F232C mutation results in the spontaneous homodimerization of CRLF2F232C and constitutive phosphorylation and activation of JAK2 and STAT5, independent of TSLP or IL-7Rα [123]. Moreover, the expression of CRLF2F232C was able to transform cytokine-dependent cell lines to cytokine-independent proliferation in vitro, suggesting a role of CRLF2 gain-of-function alterations in malignant transformation [123,124,126,128].

3. The Role of IL-7 Signaling in Other Lymphoid Malignancies

The deregulation of the IL-7 signaling pathway is frequently observed in T-ALL and T-PLL, as well as in other T-cell malignancies in particular and lymphoid malignancies in general. Indeed, stimulation with IL-7 promoted the proliferation of cutaneous T-cell lymphoma (CTCL) cells, and also Sézary lymphoma cells were sensitive to IL-7 [129,130]. In addition, IL-7 signaling is suggested to be involved in chronic lymphoid leukemia (CLL) and Hodgkin’s lymphoma, and stimulation of CLL cells with IL-7 resulted in increased proliferation in vitro [131,132].
Furthermore, gain-of-function alterations in the IL-7 signaling pathway were identified in the majority of T-cell lymphomas (reviewed by Waldmann and colleagues) [133]. Similar to ALL, mutations in JAK1 and JAK3 are mainly found in the pseudokinase domain and in STAT5B the p.N642H SH2 domain mutation frequently occurs [133]. Activating mutations in JAK1 are found in CTCL, natural killer cell lymphoma (NKCL) and large granulocytic leukemia (LGL), as well as in 20% of ALK-negative anaplastic large cell lymphoma (ALCL), and treatment with ruxolitinib reduced tumor growth in an ALK-negative ALCL PDX model in vivo [133,134]. About one third of patients with NKCL carry JAK3 gain-of-function alterations, and a NKCL PDX model was sensitive to tofacitinib, with delayed tumor growth upon treatment [135,136]. JAK3 mutations are also found in CTCL, LGL, peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and human T cell lymphotropic virus 1-associated adult T cell leukemia/lymphoma [133]. The STAT5B p.N642H gain-of-function mutation, as well as other SH2 domain mutations, were identified in CTCL, NKCL, LGL, enteropathy-associated T cell lymphoma and γδ T cell lymphoma and, like in ALL, resulted in increased STAT5B phosphorylation and transcriptional activity [133,137,138]. Moreover, in addition to TLX1+ T-ALL, bi-allelic deletions of the entire PTPN2 gene locus were identified in the Hodgkin’s lymphoma cell line SUP-HD1 and in 2 out of 39 patients with PTCL-NOS [139].

4. Therapeutic Targeting of the IL-7 Signaling Pathway in Lymphoid Malignancies

The gain-of-function alterations in the IL-7 signaling pathway provide new therapeutic targets for the treatment of ALL and other lymphoid malignancies [2,140]. In B-ALL, IL-7Rα expression is directly correlated with central nervous system (CNS) involvement at diagnosis, and the treatment of PDX models with a commercially available mouse antibody targeting IL-7Rα was able to substantially reduce leukemic cell infiltration in the CNS and prolong survival [141]. In addition, the delivery of a cytotoxic agent using a mouse anti-IL-7Rα antibody efficiently eliminated IL-7-induced glucocorticoid-resistant cells in a syngeneic mouse model [142]. Recently, Akkapeddi et al., and Hixon and colleagues developed human and chimeric mouse–human monoclonal antibodies targeting IL-7Rα, which induced antibody-dependent cell-mediated cytotoxicity against T-ALL cells in vitro and were effective for treating T-ALL in PDX models of both established and relapsed disease in vivo [143,144]. A phase I clinical trial already suggested that these therapeutic antibodies are well tolerated in healthy volunteers, and their efficacy will be further investigated in patients with T-ALL [57]. Treatment with the reducing agent N-acetylcysteine was able to inhibit spontaneous disulfide bond formation between mutant IL-7Rα chains and, as such, reduced constitutive IL-7R signaling, thereby promoting apoptosis of IL-7Rα mutant cells in vitro and reducing leukemic burden in vivo [145].
Another therapeutic strategy is to target downstream signaling molecules and/or target genes. The selective JAK1/JAK2 inhibitor ruxolitinib, which is FDA approved for the treatment of myelofibrosis and polycythemia vera, as well as other small molecule JAK inhibitors showed efficacy in pre-clinical studies using in vitro and in vivo models of T-cell malignancy and B-ALL [24,56,65,67,70,71,72,85,94,95,104,105,146]. Phase I/II and phase II/III clinical trials with ruxolitinib for the treatment of ALL are currently ongoing, and given the therapeutic benefit, St. Jude Children’s Research Hospital has recently incorporated ruxolitinib into the induction therapy of ETP-ALL (NCT03117751) [57]. Moreover, gain-of-function alterations in the IL-7 pathway also result in the activation of PI3K-AKT and Ras-MAPK signaling, and although treatment with small molecule inhibitors targeting PI3K, AKT or MEK alone were not effective, inhibiting both the PI3K-AKT and Ras-MAPK pathway synergistically reduced the cytokine-independent proliferation of Ba/F3 cells expressing mutant IL-7Rα, JAK1 or JAK3, as well as primary T-ALL cells [24].
IL-7 signaling results in the upregulation of STAT5 target genes, including BCL2 and PIM1, which are required for IL-7-mediated T-ALL cell survival [17]. Primary patient-derived T-ALL cells carrying activating JAK3 mutations showed increased sensitivity, ex vivo and in vivo, to combination treatment with the selective JAK1/JAK3 inhibitor tofacitinib and the selective BCL2 inhibitor venetoclax than to one of the inhibitors alone [147]. Similar results were obtained for in vitro and in vivo treatment of the D1 thymocyte cell line expressing mutant IL-7Rα with ruxolitinib and venetoclax [71]. Treatment with both ruxolitinib and a selective PIM1 inhibitor synergistically reduced the proliferation of an IL-7Rα mutant T-ALL cell line in vitro and leukemic burden in a PDX model of JAK3 mutant T-ALL in vivo [98].

5. Conclusions

The IL-7 signaling pathway is critical for normal lymphoid development and it is therefore not surprising that this pathway is deregulated in various lymphoid malignancies. Perhaps the most important biological lesson to learn from all these studies is that, typically, more than one gain-of-function genetic alteration is present in the IL-7 signaling pathway, indicating that a strong control mechanism is present, which cancer cells are able to overcome by acquiring multiple mutations. Considering clinical applications, these studies have taught us that JAK1 plays a central role in the mutant IL-7 signaling pathway, and that JAK1 inhibitors such as ruxolitinib could play a role in further improving the treatment of lymphoid malignancies with IL-7 signaling pathway mutations.

Author Contributions

I.L. and J.C. wrote the manuscript and approved its final version. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


We thank somersault1824 for designing the figures. J.C. is funded by VIB, KU Leuven, Stichting Tegen Kanker and Kom op Tegen Kanker.

Conflicts of Interest

We declare no competing interest.


  1. Mazzucchelli, R.; Durum, S.K. Interleukin-7 Receptor Expression: Intelligent Design. Nat. Rev. Immunol. 2007, 7, 144–154. [Google Scholar] [CrossRef]
  2. Oliveira, M.L.; Akkapeddi, P.; Ribeiro, D.; Melão, A.; Barata, J.T. IL-7R-Mediated Signaling in T-Cell Acute Lymphoblastic Leukemia: An Update. Adv. Biol. Regul. 2019, 71, 88–96. [Google Scholar] [CrossRef] [PubMed]
  3. Von Freeden-Jeffry, U.; Vieira, P.; Lucian, L.A.; McNeil, T.; Burdach, S.E.G.; Murray, R. Lymphopenia in Interleukin (IL)-7 Gene-Deleted Mice Identifies IL-7 as a Nonredundant Cytokine. J. Exp. Med. 1995, 181, 1519–1526. [Google Scholar] [CrossRef] [PubMed]
  4. Peschon, J.J.; Morrissey, P.J.; Grabstein, K.H.; Ramsdell, F.J.; Maraskovsky, E.; Gliniak, B.C.; Park, L.S.; Ziegler, S.F.; Williams, D.E.; Ware, C.B.; et al. Early Lymphocyte Expansion Is Severely Impaired in Interleukin 7 Receptor-Deficient Mice. J. Exp. Med. 1994, 180, 1955–1960. [Google Scholar] [CrossRef] [PubMed]
  5. Cunningham-Rundles, C.; Ponda, P.P. Molecular Defects in T- and B-Cell Primary Immunodeficiency Diseases. Nat. Rev. Immunol. 2005, 5, 880–892. [Google Scholar] [CrossRef] [PubMed]
  6. Puel, A.; Ziegler, S.F.; Buckley, R.H.; Leonard, W.J. Defective IL7R Expression in T-B+NK+ Severe Combined Immunodeficiency. Nat. Genet. 1998, 20, 394–397. [Google Scholar] [CrossRef] [PubMed]
  7. Noguchi, M.; Yi, H.; Rosenblatt, H.M.; Filipovich, A.H.; Adelstein, S.; Modi, W.S.; McBride, O.W.; Leonard, W.J. Interleukin-2 Receptor γ Chain Mutation Results in X-Linked Severe Combined Immunodeficiency in Humans. Cell 1993, 73, 147–157. [Google Scholar] [CrossRef]
  8. Buckley, R.H. Molecular Defects in Human Severe Combined Immunodeficiency and Approaches to Immune Reconstitution. Annu. Rev. Immunol. 2004, 22, 625–655. [Google Scholar] [CrossRef]
  9. Fry, T.J.; Mackall, C.L. Interleukin-7: From Bench to Clinic. Blood 2002, 99, 3892–3904. [Google Scholar] [CrossRef]
  10. Barata, J.T.; Cardoso, A.A.; Boussiotis, V.A. Interleukin-7 in T-Cell Acute Lymphoblastic Leukemia: An Extrinsic Factor Supporting Leukemogenesis? Leuk. Lymphoma 2005, 46, 483–495. [Google Scholar] [CrossRef]
  11. Fry, T.J.; Mackall, C.L. The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance. J. Immunol. 2005, 174, 6571–6576. [Google Scholar] [CrossRef] [PubMed]
  12. Munitic, I.; Williams, J.A.; Yang, Y.; Dong, B.; Lucas, P.J.; El Kassar, N.; Gress, R.E.; Ashwell, J.D. Dynamic Regulation of IL-7 Receptor Expression Is Required for Normal Thymopoiesis. Blood 2004, 104, 4165–4172. [Google Scholar] [CrossRef] [PubMed]
  13. Park, J.-H.; Yu, Q.; Erman, B.; Appelbaum, J.S.; Montoya-Durango, D.; Grimes, H.L.; Singer, A. Suppression of IL7Ralpha Transcription by IL-7 and Other Prosurvival Cytokines: A Novel Mechanism for Maximizing IL-7-Dependent T Cell Survival. Immunity 2004, 21, 289–302. [Google Scholar] [CrossRef] [PubMed]
  14. Kittipatarin, C.; Khaled, A.R. Interlinking Interleukin-7. Cytokine 2007, 39, 75–83. [Google Scholar] [CrossRef]
  15. Palmer, M.J.; Mahajan, V.S.; Trajman, L.C.; Irvine, D.J.; Lauffenburger, D.A.; Chen, J. Interleukin-7 Receptor Signaling Network: An Integrated Systems Perspective. Cell. Mol. Immunol. 2008, 5, 79–89. [Google Scholar] [CrossRef]
  16. Ribeiro, D.; Melão, A.; Barata, J.T. IL-7R-Mediated Signaling in T-Cell Acute Lymphoblastic Leukemia. Adv. Biol. Regul. 2013, 53, 211–222. [Google Scholar] [CrossRef] [PubMed]
  17. Ribeiro, D.; Melão, A.; van Boxtel, R.; Santos, C.I.; Silva, A.; Silva, M.C.; Cardoso, B.A.; Coffer, P.J.; Barata, J.T. STAT5 Is Essential for IL-7–Mediated Viability, Growth, and Proliferation of T-Cell Acute Lymphoblastic Leukemia Cells. Blood Adv. 2018, 2, 2199–2213. [Google Scholar] [CrossRef]
  18. Levy, D.E.; Darnell, J.E. STATs: Transcriptional Control and Biological Impact. Nat. Rev. Mol. Cell Biol. 2002, 3, 651–662. [Google Scholar] [CrossRef]
  19. Jiang, Q.; Li, W.Q.; Hofmeister, R.R.; Young, H.A.; Hodge, D.R.; Keller, J.R.; Khaled, A.R.; Durum, S.K. Distinct Regions of the Interleukin-7 Receptor Regulate Different Bcl2 Family Members. Mol. Cell. Biol. 2004, 24, 6501–6513. [Google Scholar] [CrossRef] [PubMed]
  20. Le Saout, C.; Luckey, M.A.; Villarino, A.V.; Smith, M.; Hasley, R.B.; Myers, T.G.; Imamichi, H.; Park, J.H.; O’Shea, J.J.; Lane, H.C.; et al. IL-7-Dependent STAT1 Activation Limits Homeostatic CD4+ T Cell Expansion. JCI Insight 2017, 2, 1–18. [Google Scholar] [CrossRef]
  21. Lu, N.; Wang, Y.H.; Wang, Y.H.; Arima, K.; Hanabuchi, S.; Liu, Y.J. TSLP and IL-7 Use Two Different Mechanisms to Regulate Human CD4 + T Cell Homeostasis. J. Exp. Med. 2009, 206, 2111–2119. [Google Scholar] [CrossRef] [PubMed]
  22. Rochman, Y.; Kashyap, M.; Robinson, G.W.; Sakamoto, K.; Gomez-Rodriguez, J.; Wagner, K.U.; Leonard, W.J. Thymic Stromal Lymphopoietin-Mediated STAT5 Phosphorylation via Kinases JAK1 and JAK2 Reveals a Key Difference from IL-7-Induced Signaling. Proc. Natl. Acad. Sci. USA 2010, 107, 19455–19460. [Google Scholar] [CrossRef]
  23. Barata, J.T.; Silva, A.; Brandao, J.G.; Nadler, L.M.; Cardoso, A.A.; Boussiotis, V.A. Activation of PI3K Is Indispensable for Interleukin 7-Mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells. J. Exp. Med. 2004, 200, 659–669. [Google Scholar] [CrossRef]
  24. Canté-Barrett, K.; Spijkers-Hagelstein, J.A.P.; Buijs-Gladdines, J.G.C.A.M.; Uitdehaag, J.C.M.; Smits, W.K.; Van Der Zwet, J.; Buijsman, R.C.; Zaman, G.J.R.; Pieters, R.; Meijerink, J.P.P. MEK and PI3K-AKT Inhibitors Synergistically Block Activated IL7 Receptor Signaling in T-Cell Acute Lymphoblastic Leukemia. Leukemia 2016, 30, 1832–1843. [Google Scholar] [CrossRef] [PubMed]
  25. Winston, L.A.; Hunter, T. Intracellular Signalling: Putting JAKs on the Kinase MAP. Curr. Biol. 1996, 6, 668–671. [Google Scholar] [CrossRef]
  26. Benbernou, N.; Muegge, K.; Durum, S.K. Interleukin (IL)-7 Induces Rapid Activation of Pyk2, Which Is Bound to Janus Kinase 1 and IL-7Rα. J. Biol. Chem. 2000, 275, 7060–7065. [Google Scholar] [CrossRef]
  27. Kang, J.; Der, S.D. Cytokine Functions in the Formative Stages of a Lymphocyte’s Life. Curr. Opin. Immunol. 2004, 16, 180–190. [Google Scholar] [CrossRef] [PubMed]
  28. Jiang, Q.; Wen, Q.L.; Aiello, F.B.; Mazzucchelli, R.; Asefa, B.; Khaled, A.R.; Durum, S.K. Cell Biology of IL-7, a Key Lymphotrophin. Cytokine Growth Factor Rev. 2005, 16, 513–533. [Google Scholar] [CrossRef] [PubMed]
  29. Bousoik, E.; Montazeri Aliabadi, H. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway. Front. Oncol. 2018, 8, 1–20. [Google Scholar] [CrossRef]
  30. Vainchenker, W.; Constantinescu, S.N. JAK/STAT Signaling in Hematological Malignancies. Oncogene 2013, 32, 2601–2613. [Google Scholar] [CrossRef]
  31. Shuai, K.; Liu, B. Regulation of JAK-STAT Signalling in the Immune System. Nat. Rev. Immunol. 2003, 3, 900–911. [Google Scholar] [CrossRef]
  32. Pandey, A.; Ozaki, K.; Baumann, H.; Levin, S.D.; Puel, A.; Farr, A.G.; Ziegler, S.F.; Leonard, W.J.; Lodish, H.F. Cloning of a Receptor Subunit Required for Signaling by Thymic Stromal Lymphopoietin. Nat. Immunol. 2000, 1, 59–64. [Google Scholar] [CrossRef]
  33. Park, L.S.; Martin, U.; Garka, K.; Gliniak, B.; Di Santo, J.P.; Muller, W.; Largaespada, D.A.; Copeland, N.G.; Jenkins, N.A.; Farr, A.G.; et al. Cloning of the Murine Thymic Stromal Lymphopoietin (TSLP) Receptor: Formation of a Functional Heteromeric Complex Requires Interleukin 7 Receptor. J. Exp. Med. 2000, 192, 659–670. [Google Scholar] [CrossRef]
  34. Isaksen, D.E.; Baumann, H.; Trobridge, P.A.; Farr, A.G.; Levin, S.D.; Ziegler, S.F. Requirement for Stat5 in Thymic Stromal Lymphopoietin-Mediated Signal Transduction. J. Immunol. 1999, 163, 5971–5977. [Google Scholar]
  35. Ziegler, S.F.; Liu, Y.J. Thymic Stromal Lymphopoietin in Normal and Pathogenic T Cell Development and Function. Nat. Immunol. 2006, 7, 709–714. [Google Scholar] [CrossRef] [PubMed]
  36. Hofmeister, R.; Khaled, A.R.; Benbernou, N.; Rajnavolgyi, E.; Muegge, K.; Durum, S.K. Interleukin-7: Physiological Roles and Mechanisms of Action. Cytokine Growth Factor Rev. 1999, 10, 41–60. [Google Scholar] [CrossRef]
  37. Sims, J.E.; Williams, D.E.; Morrissey, P.J.; Garka, K.; Foxworthe, D.; Price, V.; Friend, S.L.; Farr, A.; Bedell, M.A.; Jenkins, N.A.; et al. Molecular Cloning and Biological Characterization of a Novel Murine Lymphoid Growth Factor. J. Exp. Med. 2000, 192, 671–680. [Google Scholar] [CrossRef] [PubMed]
  38. Levin, S.D.; Koelling, R.M.; Friend, S.L.; Isaksen, D.E.; Ziegler, S.F.; Perlmutter, R.M.; Farr, A.G. Thymic Stromal Lymphopoietin: A Cytokine That Promotes the Development of IgM+ B Cells in Vitro and Signals via a Novel Mechanism. J. Immunol. 1999, 162, 677–683. [Google Scholar]
  39. Vosshenrich, C.A.J.; Cumano, A.; Müller, W.; Di Santo, J.P.; Vieira, P. Thymic Stromal-Derived Lymphopoietin Distinguishes Fetal from Adult B Cell Development. Nat. Immunol. 2003, 4, 773–779. [Google Scholar] [CrossRef]
  40. Vosshenrich, C.A.J.; Cumano, A.; Müller, W.; Di Santo, J.P.; Vieira, P. Pre-B Cell Receptor Expression Is Necessary for Thymic Stromal Lymphopoietin Responsiveness in the Bone Marrow but Not in the Liver Environment. Proc. Natl. Acad. Sci. USA 2004, 101, 11070–11075. [Google Scholar] [CrossRef]
  41. Al-Shami, A.; Spolski, R.; Kelly, J.; Fry, T.; Schwartzberg, P.L.; Pandey, A.; Mackall, C.L.; Leonard, W.J. A Role for Thymic Stromal Lymphopoietin in CD4(+) T Cell Development. J. Exp. Med. 2004, 200, 159–168. [Google Scholar] [CrossRef] [PubMed]
  42. Reche, P.A.; Soumelis, V.; Gorman, D.M.; Clifford, T.; Liu, M.; Travis, M.; Zurawski, S.M.; Johnston, J.; Liu, Y.-J.; Spits, H.; et al. Human Thymic Stromal Lymphopoietin Preferentially Stimulates Myeloid Cells. J. Immunol. 2001, 167, 336–343. [Google Scholar] [CrossRef]
  43. Soumelis, V.; Reche, P.A.; Kanzler, H.; Yuan, W.; Edward, G.; Homey, B.; Gilliet, M.; Ho, S.; Antonenko, S.; Lauerma, A.; et al. Human Epithelial Cells Trigger Dendritic Cell–Mediated Allergic Inflammation by Producing TSLP. Nat. Immunol. 2002, 3, 673–680. [Google Scholar] [CrossRef]
  44. Brocker, T. Survival of Mature CD4 T Lymphocytes Is Dependent on Major Histocompatibility Complex Class II-Expressing Dendritic Cells. J. Exp. Med. 1997, 186, 1223–1232. [Google Scholar] [CrossRef]
  45. Ge, Q.; Palliser, D.; Eisen, H.N.; Chen, J. Homeostatic T Cell Proliferation in a T Cell-Dendritic Cell Coculture System. Proc. Natl. Acad. Sci. USA 2002, 99, 2983–2988. [Google Scholar] [CrossRef] [PubMed]
  46. Watanabe, N.; Hanabuchi, S.; Soumelis, V.; Yuan, W.; Ho, S.; de Waal Malefyt, R.; Liu, Y.-J. Human Thymic Stromal Lymphopoietin Promotes Dendritic Cell-Mediated CD4+ T Cell Homeostatic Expansion. Nat. Immunol. 2004, 5, 426–434. [Google Scholar] [CrossRef]
  47. Watanabe, N.; Wang, Y.-H.; Lee, H.K.; Ito, T.; Wang, Y.-H.; Cao, W.; Liu, Y.-J. Hassall’s Corpuscles Instruct Dendritic Cells to Induce CD4+CD25+ Regulatory T Cells in Human Thymus. Nature 2005, 436, 1181–1185. [Google Scholar] [CrossRef]
  48. Carpino, N.; Thierfelder, W.E.; Chang, M.; Saris, C.; Turner, S.J.; Ziegler, S.F.; Ihle, J.N. Absence of an Essential Role for Thymic Stromal Lymphopoietin Receptor in Murine B-Cell Development. Mol. Cell. Biol. 2004, 24, 2584–2592. [Google Scholar] [CrossRef]
  49. Giliani, S.; Mori, L.; de Saint Basile, G.; Le Deist, F.; Rodriguez-Perez, C.; Forino, C.; Mazzolari, E.; Dupuis, S.; Elhasid, R.; Kessel, A.; et al. Interleukin-7 Receptor Alpha (IL-7Ralpha) Deficiency: Cellular and Molecular Bases. Analysis of Clinical, Immunological, and Molecular Features in 16 Novel Patients. Immunol. Rev. 2005, 203, 110–126. [Google Scholar] [CrossRef] [PubMed]
  50. Abraham, N.; Ma, M.C.; Snow, J.W.; Miners, M.J.; Herndier, B.G.; Goldsmith, M.A. Haploinsufficiency Identifies STATS as a Modifier of IL-7-Induced Lymphomas. Oncogene 2005, 24, 5252–5257. [Google Scholar] [CrossRef] [PubMed]
  51. Osborne, L.C.; Duthie, K.A.; Seo, J.H.; Gascoyne, R.D.; Abraham, N. Selective Ablation of the YxxM Motif of IL-7Rα Suppresses Lymphomagenesis but Maintains Lymphocyte Development. Oncogene 2010, 29, 3854–3864. [Google Scholar] [CrossRef]
  52. Laouar, Y.; Crispe, I.N.; Flavell, R.A. Overexpression of IL-7Rα Provides a Competitive Advantage during Early T-Cell Development. Blood 2004, 103, 1985–1994. [Google Scholar] [CrossRef]
  53. Rich, B.E.; Campos-Torres, J.; Tepper, R.I.; Moreadith, R.W.; Leder, P. Cutaneous Lymphoproliferation and Lymphomas in Interleukin 7 Transgenic Mice. J. Exp. Med. 1993, 177, 305–316. [Google Scholar] [CrossRef] [PubMed]
  54. Silva, A.; Laranjeira, A.B.A.; Martins, L.R.; Cardoso, B.A.; Demengeot, J.; Andrés Yunes, J.; Seddon, B.; Barata, J.T. IL-7 Contributes to the Progression of Human T-Cell Acute Lymphoblastic Leukemias. Cancer Res. 2011, 71, 4780–4789. [Google Scholar] [CrossRef]
  55. Karawajew, L.; Ruppert, V.; Wuchter, C.; Kösser, A.; Schrappe, M.; Dörken, B.; Ludwig, W.D. Inhibition of in Vitro Spontaneous Apoptosis by IL-7 Correlates, with Bcl-2 up-Regulation, Cortical/Mature Immunophenotype, and Better Early Cytoreduction of Childhood T-Cell Acute Lymphoblastic Leukemia. Blood 2000, 96, 297–306. [Google Scholar] [CrossRef]
  56. Maude, S.L.; Tasian, S.K.; Vincent, T.; Hall, J.W.; Sheen, C.; Roberts, K.G.; Seif, A.E.; Barrett, D.M.; Chen, I.M.; Collins, J.R.; et al. Targeting JAK1/2 and MTOR in Murine Xenograft Models of Ph-like Acute Lymphoblastic Leukemia. Blood 2012, 120, 3510–3518. [Google Scholar] [CrossRef]
  57. Barata, J.T.; Durum, S.K.; Seddon, B. Flip the Coin: IL-7 and IL-7R in Health and Disease. Nat. Immunol. 2019, 20, 1584–1593. [Google Scholar] [CrossRef]
  58. González-García, S.; Mosquera, M.; Fuentes, P.; Palumbo, T.; Escudero, A.; Pérez-Martínez, A.; Ramírez, M.; Corcoran, A.E.; Toribio, M.L. IL-7R Is Essential for Leukemia-Initiating Cell Activity of T-Cell Acute Lymphoblastic Leukemia. Blood 2019, 134, 2171–2182. [Google Scholar] [CrossRef] [PubMed]
  59. Goossens, S.; Radaelli, E.; Blanchet, O.; Durinck, K.; Van Der Meulen, J.; Peirs, S.; Taghon, T.; Tremblay, C.S.; Costa, M.; Ghahremani, M.F.; et al. ZEB2 Drives Immature T-Cell Lymphoblastic Leukaemia Development via Enhanced Tumour-Initiating Potential and IL-7 Receptor Signalling. Nat. Commun. 2015, 6. [Google Scholar] [CrossRef] [PubMed]
  60. Girardi, T.; Vereecke, S.; Sulima, S.O.; Khan, Y.; Fancello, L.; Briggs, J.W.; Schwab, C.; De Beeck, J.O.; Verbeeck, J.; Royaert, J.; et al. The T-Cell Leukemia-Associated Ribosomal RPL10 R98S Mutation Enhances JAK-STAT Signaling. Leukemia 2018, 32, 809–819. [Google Scholar] [CrossRef]
  61. Sharma, N.D.; Nickl, C.K.; Kang, H.; Ornatowski, W.; Brown, R.; Ness, S.A.; Loh, M.L.; Mullighan, C.G.; Winter, S.S.; Hunger, S.P.; et al. Epigenetic Silencing of SOCS5 Potentiates JAK-STAT Signaling and Progression of T-Cell Acute Lymphoblastic Leukemia. Cancer Sci. 2019, 110, 1931–1946. [Google Scholar] [CrossRef]
  62. Goodwin, R.G.; Friend, D.; Ziegler, S.F.; Jerzy, R.; Falk, B.A.; Gimpel, S.; Cosman, D.; Dower, S.K.; March, C.J.; Namen, A.E.; et al. Cloning of the Human and Murine Interleukin-7 Receptors: Demonstration of a Soluble Form and Homology to a New Receptor Superfamily. Cell 1990, 60, 941–951. [Google Scholar] [CrossRef]
  63. McElroy, C.A.; Dohm, J.A.; Walsh, S.T.R. Structural and Biophysical Studies of the Human IL-7/IL-7Rα Complex. Structure 2009, 17, 54–65. [Google Scholar] [CrossRef]
  64. Campos, L.W.; Pissinato, L.G.; Yunes, J.A. Deleterious and Oncogenic Mutations in the Il7ra. Cancers 2019, 11, 1952. [Google Scholar] [CrossRef]
  65. Zenatti, P.P.; Ribeiro, D.; Li, W.; Zuurbier, L.; Silva, M.C.; Paganin, M.; Tritapoe, J.; Hixon, J.A.; Silveira, A.B.; Cardoso, B.A.; et al. Oncogenic IL7R Gain-of-Function Mutations in Childhood T-Cell Acute Lymphoblastic Leukemia. Nat. Genet. 2011, 43, 932–941. [Google Scholar] [CrossRef] [PubMed]
  66. Shochat, C.; Tal, N.; Bandapalli, O.R.; Palmi, C.; Ganmore, I.; te Kronnie, G.; Cario, G.; Cazzaniga, G.; Kulozik, A.E.; Stanulla, M.; et al. Gain-of-Function Mutations in Interleukin-7 Receptor-α (IL7R) in Childhood Acute Lymphoblastic Leukemias. J. Exp. Med. 2011, 208, 901–908. [Google Scholar] [CrossRef]
  67. Zhang, J.; Ding, L.; Holmfeldt, L.; Wu, G.; Heatley, S.L.; Payne-Turner, D.; Easton, J.; Chen, X.; Wang, J.; Rusch, M.; et al. The Genetic Basis of Early T-Cell Precursor Acute Lymphoblastic Leukaemia. Nature 2012, 481, 157–163. [Google Scholar] [CrossRef]
  68. Roberts, K.G.; Li, Y.; Payne-Turner, D.; Harvey, R.C.; Yang, Y.L.; Pei, D.; McCastlain, K.; Ding, L.; Lu, C.; Song, G.; et al. Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2014, 371, 1005–1015. [Google Scholar] [CrossRef] [PubMed]
  69. Roberts, K.G.; Morin, R.D.; Zhang, J.; Hirst, M.; Zhao, Y.; Su, X.; Chen, S.C.; Payne-Turner, D.; Churchman, M.L.; Harvey, R.C.; et al. Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia. Cancer Cell 2012, 22, 153–166. [Google Scholar] [CrossRef]
  70. Roberts, K.G.; Yang, Y.L.; Payne-Turner, D.; Lin, W.; Files, J.K.; Dickerson, K.; Gu, Z.; Taunton, J.; Janke, L.J.; Chen, T.; et al. Oncogenic Role and Therapeutic Targeting of ABL-Class and JAK-STAT Activating Kinase Alterations in Ph-like ALL. Blood Adv. 2017, 1, 1657–1671. [Google Scholar] [CrossRef] [PubMed]
  71. Senkevitch, E.; Li, W.; Hixon, J.A.; Andrews, C.; Cramer, S.D.; Pauly, G.T.; Back, T.; Czarra, K.; Durum, S.K. Inhibiting Janus Kinase 1 and BCL-2 to Treat T Cell Acute Lymphoblastic Leukemia with IL7-Rα Mutations. Oncotarget 2018, 9, 22605–22617. [Google Scholar] [CrossRef]
  72. Treanor, L.M.; Zhou, S.; Janke, L.; Churchman, M.L.; Ma, Z.; Lu, T.; Chen, S.C.; Mullighan, C.G.; Sorrentino, B.P. Interleukin-7 Receptor Mutants Initiate Early t Cell Precursor Leukemia in Murine Thymocyte Progenitors with Multipotent Potential. J. Exp. Med. 2014, 211, 701–713. [Google Scholar] [CrossRef] [PubMed]
  73. Campos, L.W.; Zenatti, P.P.; Pissinato, L.G.; Rodrigues, G.O.L.; Artico, L.L.; Guimarães, T.R.; Archangelo, L.F.; Martínez, L.; Brooks, A.J.; Yunes, J.A. Oncogenic Basic Amino Acid Insertions at the Extracellular Juxtamembrane Region of IL7RA Cause Receptor Hypersensitivity. Blood 2019, 133, 1259–1263. [Google Scholar] [CrossRef]
  74. Russ, W.P.; Engelman, D.M. The GxxxG Motif: A Framework for Transmembrane Helix-Helix Association. J. Mol. Biol. 2000, 296, 911–919. [Google Scholar] [CrossRef] [PubMed]
  75. Ridder, A.; Skupjen, P.; Unterreitmeier, S.; Langosch, D. Tryptophan Supports Interaction of Transmembrane Helices. J. Mol. Biol. 2005, 354, 894–902. [Google Scholar] [CrossRef] [PubMed]
  76. Shochat, C.; Tal, N.; Gryshkova, V.; Birger, Y.; Bandapalli, O.R.; Cazzaniga, G.; Gershman, N.; Kulozik, A.E.; Biondi, A.; Mansour, M.R.; et al. Novel Activating Mutations Lacking Cysteine in Type i Cytokine Receptors in Acute Lymphoblastic Leukemia. Blood 2014, 124, 106–110. [Google Scholar] [CrossRef]
  77. Kiel, M.J.; Velusamy, T.; Rolland, D.; Sahasrabuddhe, A.A.; Chung, F.; Bailey, N.G.; Schrader, A.; Li, B.; Li, J.Z.; Ozel, A.B.; et al. Integrated Genomic Sequencing Reveals Mutational Landscape of T-Cell Prolymphocytic Leukemia. Blood 2014, 124, 1460–1472. [Google Scholar] [CrossRef]
  78. Chen, M.; Cheng, A.; Chen, Y.-Q.; Hymel, A.; Hanson, E.P.; Kimmel, L.; Minami, Y.; Taniguchi, T.; Changelian, P.S.; O’Shea, J.J. The Amino Terminus of JAK3 Is Necessary and Sufficient for Binding to the Common γ Chain and Confers the Ability to Transmit Interleukin 2-Mediated Signals. Proc. Natl. Acad. Sci. USA 1997, 94, 6910–6915. [Google Scholar] [CrossRef]
  79. Zhao, Y.; Wagner, F.; Frank, S.J.; Kraft, A.S. The Amino-Terminal Portion of the JAK2 Protein Kinase Is Necessary For Binding and Phosphorylation of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor β Chain*. J. Biol. Chem. 1995, 270, 13814–13818. [Google Scholar] [CrossRef]
  80. Hornakova, T.; Springuel, L.; Devreux, J.; Dusa, A.; Constantinescu, S.N.; Knoops, L.; Renauld, J.C. Oncogenic JAK1 and JAK2-Activating Mutations Resistant to ATP-Competitive Inhibitors. Haematologica 2011, 96, 845–853. [Google Scholar] [CrossRef] [PubMed]
  81. Staerk, J.; Kallin, A.; Demoulin, J.B.; Vainchenker, W.; Constantinescu, S.N. JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation: Cross-Talk with IGF1 Receptor. J. Biol. Chem. 2005, 280, 41893–41899. [Google Scholar] [CrossRef] [PubMed]
  82. Gordon, G.M.; Lambert, Q.T.; Daniel, K.G.; Reuther, G.W. Transforming JAK1 Mutations Exhibit Differential Signalling, FERM Domain Requirements and Growth Responses to Interferon-γ. Biochem. J. 2010, 432, 255–265. [Google Scholar] [CrossRef] [PubMed]
  83. Flex, E.; Petrangeli, V.; Stella, L.; Chiaretti, S.; Hornakova, T.; Knoops, L.; Ariola, C.; Fodale, V.; Clappier, E.; Paoloni, F.; et al. Somatically Acquired JAK1 Mutations in Adult Acute Lymphoblastic Leukemia. J. Exp. Med. 2008, 205, 751–758. [Google Scholar] [CrossRef] [PubMed]
  84. Yin, C.; Sandoval, C.; Baeg, G.H. Identification of Mutant Alleles of JAK3 in Pediatric Patients with Acute Lymphoblastic Leukemia. Leuk. Lymphoma 2015, 56, 1502–1506. [Google Scholar] [CrossRef]
  85. Mullighan, C.G.; Zhang, J.; Harvey, R.C.; Collins-Underwood, J.R.; Schulman, B.A.; Phillips, L.A.; Tasian, S.K.; Loh, M.L.; Su, X.; Liu, W.; et al. JAK Mutations in High-Risk Childhood Acute Lymphoblastic Leukemia. Proc. Natl. Acad. Sci. USA 2009, 106, 9414–9418. [Google Scholar] [CrossRef]
  86. Asnafi, V.; Le Noir, S.; Lhermitte, L.; Gardin, C.; Legrand, F.; Vallantin, X.; Malfuson, J.V.; Ifrah, N.; Dombret, H.; MacIntyre, E. JAK1 Mutations Are Not Frequent Events in Adult T-ALL: A GRAALL Study. Br. J. Haematol. 2010, 148, 178–179. [Google Scholar] [CrossRef] [PubMed]
  87. Li, Q.; Li, B.; Hu, L.; Ning, H.; Jiang, M.; Wang, D.; Liu, T.; Zhang, B.; Chen, H. Identification of a Novel Functional JAK1 S646P Mutation in Acute Lymphoblastic Leukemia. Oncotarget 2017, 8, 34687–34697. [Google Scholar] [CrossRef] [PubMed]
  88. Jeong, E.G.; Kim, M.S.; Nam, H.K.; Min, C.K.; Lee, S.; Chung, Y.J.; Yoo, N.J.; Lee, S.H. Somatic Mutations of JAK1 and JAK3 in Acute Leukemias and Solid Cancers. Clin. Cancer Res. 2008, 14, 3716–3721. [Google Scholar] [CrossRef] [PubMed]
  89. Vicente, C.; Schwab, C.; Broux, M.; Geerdens, E.; Degryse, S.; Demeyer, S.; Lahortiga, I.; Elliott, A.; Chilton, L.; La Starza, R.; et al. Targeted Sequencing Identifies Associations between IL7R-JAK Mutations and Epigenetic Modulators in T-Cell Acute Lymphoblastic Leukemia. Haematologica 2015, 100, 1301–1310. [Google Scholar] [CrossRef]
  90. Liu, Y.; Easton, J.; Shao, Y.; Maciaszek, J.; Wang, Z.; Wilkinson, M.R.; McCastlain, K.; Edmonson, M.; Pounds, S.B.; Shi, L.; et al. The Genomic Landscape of Pediatric and Young Adult T-Lineage Acute Lymphoblastic Leukemia. Nat. Genet. 2017, 49, 1211–1218. [Google Scholar] [CrossRef]
  91. Elliott, N.E.; Cleveland, S.M.; Grann, V.; Janik, J.; Waldmann, T.A.; Davé, U.P. FERM Domain Mutations Induce Gain of Function in JAK3 in Adult T-Cell Leukemia/Lymphoma. Blood 2011, 118, 3911–3921. [Google Scholar] [CrossRef]
  92. Bains, T.; Heinrich, M.C.; Loriaux, M.M.; Beadling, C.; Nelson, D.; Warrick, A.; Neff, T.L.; Tyner, J.W.; Dunlap, J.; Corless, C.L.; et al. Newly Described Activating JAK3 Mutations in T-Cell Acute Lymphoblastic Leukemia. Leukemia 2012, 26, 2144–2146. [Google Scholar] [CrossRef] [PubMed]
  93. Vicente, C.; Cools, J. The Origin of Relapse in Pediatric T-Cell Acute Lymphoblastic Leukemia. Haematologica 2015, 100, 1373–1375. [Google Scholar] [CrossRef] [PubMed]
  94. Degryse, S.; De Bock, C.E.; Cox, L.; Demeyer, S.; Gielen, O.; Mentens, N.; Jacobs, K.; Geerdens, E.; Gianfelici, V.; Hulselmans, G.; et al. JAK3 Mutants Transform Hematopoietic Cells through JAK1 Activation, Causing T-Cell Acute Lymphoblastic Leukemia in a Mouse Model. Blood 2014, 124, 3092–3100. [Google Scholar] [CrossRef]
  95. Losdyck, E.; Hornakova, T.; Springuel, L.; Degryse, S.; Gielen, O.; Cools, J.; Constantinescu, S.N.; Flex, E.; Tartaglia, M.; Renauld, J.C.; et al. Distinct Acute Lymphoblastic Leukemia (ALL)-Associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities. J. Biol. Chem. 2015, 290, 29022–29034. [Google Scholar] [CrossRef]
  96. Steven Martinez, G.; Ross, J.A.; Kirken, R.A. Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 Inhibitors. Clin. Cancer Drugs 2016, 3, 131–137. [Google Scholar] [CrossRef] [PubMed]
  97. Kawamura, M.; McVicar, D.W.; Johnston, J.A.; Blake, T.B.; Chen, Y.Q.; Lal, B.K.; Lloyd, A.R.; Kelvin, D.J.; Staples, J.E.; Ortaldo, J.R. Molecular Cloning of L-JAK, a Janus Family Protein-Tyrosine Kinase Expressed in Natural Killer Cells and Activated Leukocytes. Proc. Natl. Acad. Sci. USA 1994, 91, 6374–6378. [Google Scholar] [CrossRef]
  98. de Bock, C.E.; Demeyer, S.; Degryse, S.; Verbeke, D.; Sweron, B.; Gielen, O.; Vandepoel, R.; Vicente, C.; Bempt, M.V.; Dagklis, A.; et al. HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development. Cancer Discov. 2018, 8, 616–631. [Google Scholar] [CrossRef]
  99. Degryse, S.; Bornschein, S.; de Bock, C.E.; Leroy, E.; Vanden Bempt, M.; Demeyer, S.; Jacobs, K.; Geerdens, E.; Gielen, O.; Soulier, J.; et al. Mutant JAK3 Signaling Is Increased by Loss of Wild-Type JAK3 or by Acquisition of Secondary JAK3 Mutations in T-ALL. Blood 2018, 131, 421–425. [Google Scholar] [CrossRef]
  100. Hornakova, T.; Staerk, J.; Royer, Y.; Flex, E.; Tartaglia, M.; Constantinescu, S.N.; Knoops, L.; Renauld, J.C. Acute Lymphoblastic Leukemia-Associated JAK1 Mutants Activate the Janus Kinase/STAT Pathway via Interleukin-9 Receptor α Homodimers. J. Biol. Chem. 2009, 284, 6773–6781. [Google Scholar] [CrossRef]
  101. Clevenger, C.V. Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer. Am. J. Pathol. 2004, 165, 1449–1460. [Google Scholar] [CrossRef]
  102. Kontro, M.; Kuusanmäki, H.; Eldfors, S.; Burmeister, T.; Andersson, E.I.; Bruserud, Ø.; Brümmendorf, T.H.; Edgren, H.; Gjertsen, B.T.; Itälä-Remes, M.; et al. Novel Activating STAT5B Mutations as Putative Drivers of T-Cell Acute Lymphoblastic Leukemia. Leukemia 2014, 28, 1738–1742. [Google Scholar] [CrossRef] [PubMed]
  103. Bandapalli, O.R.; Schuessele, S.; Kunz, J.B.; Rausch, T.; Stütz, A.M.; Tal, N.; Geron, I.; Gershman, N.; Izraeli, S.; Eilers, J.; et al. The Activating STAT5B N642H Mutation Is a Common Abnormality in Pediatric T-Cell Acutelymphoblastic Leukemia and Confers a Higher Risk of Relapse. Haematologica 2014, 99, 188–192. [Google Scholar] [CrossRef]
  104. Govaerts, I.; Jacobs, K.; Vandepoel, R.; Cools, J. JAK/STAT Pathway Mutations in T-ALL, Including the STAT5B N642H Mutation, Are Sensitive to JAK1/JAK3 Inhibitors. HemaSphere 2019, 3, 5–8. [Google Scholar] [CrossRef]
  105. Pham, H.T.T.; Maurer, B.; Prchal-Murphy, M.; Grausenburger, R.; Grundschober, E.; Javaheri, T.; Nivarthi, H.; Boersma, A.; Kolbe, T.; Elabd, M.; et al. STAT5B N642H Is a Driver Mutation for T Cell Neoplasia. J. Clin. Investig. 2018, 128, 387–401. [Google Scholar] [CrossRef]
  106. Pike, K.A.; Tremblay, M.L. TC-PTP and PTP1B: Regulating JAK-STAT Signaling, Controlling Lymphoid Malignancies. Cytokine 2016, 82, 52–57. [Google Scholar] [CrossRef]
  107. Kleppe, M.; Lahortiga, I.; El Chaar, T.; De Keersmaecker, K.; Mentens, N.; Graux, C.; Van Roosbroeck, K.; Ferrando, A.A.; Langerak, A.W.; Meijerink, J.P.P.; et al. Deletion of the Protein Tyrosine Phosphatase Gene PTPN2 in T-Cell Acute Lymphoblastic Leukemia. Nat. Genet. 2010, 42, 530–535. [Google Scholar] [CrossRef]
  108. Alcantara, M.; Simonin, M.; Lhermitte, L.; Touzart, A.; Dourthe, M.E.; Latiri, M.; Grardel, N.; Cayuela, J.M.; Chalandon, Y.; Graux, C.; et al. Clinical and Biological Features of PTPN2-Deleted Adult and Pediatric T-Cell Acute Lymphoblastic Leukemia. Blood Adv. 2019, 3, 1981–1988. [Google Scholar] [CrossRef]
  109. Kleppe, M.; Soulier, J.; Asnafi, V.; Mentens, N.; Hornakova, T.; Knoops, L.; Constantinescu, S.; Sigaux, F.; Meijerink, J.P.; Vandenberghe, P.; et al. PTPN2 Negatively Regulates Oncogenic JAK1 in T-Cell Acute Lymphoblastic Leukemia. Blood 2011, 117, 7090–7098. [Google Scholar] [CrossRef] [PubMed]
  110. Ruela-de-Sousa, R.R.; Queiroz, K.C.S.; Peppelenbosch, M.P.; Fuhler, G.M. Reversible Phosphorylation in Haematological Malignancies: Potential Role for Protein Tyrosine Phosphatases in Treatment? Biochim. Biophys. Acta Rev. Cancer 2010, 1806, 287–303. [Google Scholar] [CrossRef] [PubMed]
  111. Kishihara, K.; Penninger, J.; Wallace, V.A.; Kündig, T.M.; Kawal, K.; Wakeham, A.; Timms, E.; Pfeffer, K.; Ohashi, P.S.; Thomas, M.L.; et al. Normal B Lymphocyte Development but Impaired T Cell Maturation in CD45-Exon6 Protein Tyrosine Phosphatase-Deficient Mice. Cell 1993, 74, 143–156. [Google Scholar] [CrossRef]
  112. Byth, K.F.; Conroy, L.A.; Howlett, S.; Smith, A.J.; May, J.; Alexander, D.R.; Holmes, N. CD45-Null Transgenic Mice Reveal a Positive Regulatory Role for CD45 in Early Thymocyte Development, in the Selection of CD4+CD8+ Thymocytes, and B Cell Maturation. J. Exp. Med. 1996, 183, 1707–1718. [Google Scholar] [CrossRef]
  113. Kung, C.; Pingel, J.T.; Heikinheimo, M.; Klemola, T.; Varkila, K.; Yoo, L.I.; Vuopala, K.; Poyhonen, M.; Uhari, M.; Rogers, M.; et al. Mutations in the Tyrosine Phosphatase CD45 Gene in a Child with Severe Combined Immunodeficiency Disease. Nat. Med. 2000, 6, 343–345. [Google Scholar] [CrossRef] [PubMed]
  114. Irie-Sasaki, J.; Sasaki, T.; Matsumoto, W.; Opavsky, A.; Cheng, M.; Welstead, G.; Griffiths, E.; Krawczyk, C.; Richardson, C.D.; Aitken, K.; et al. CD45 Is a JAK Phosphatase and Negatively Regulates Cytokine Receptor Signalling. Nature 2001, 409, 349–354. [Google Scholar] [CrossRef]
  115. Wu, L.; Bijian, K.; Shen, S.S. CD45 Recruits Adapter Protein DOK-1 and Negatively Regulates JAK-STAT Signaling in Hematopoietic Cells. Mol. Immunol. 2009, 46, 2167–2177. [Google Scholar] [CrossRef]
  116. Ratei, R.; Sperling, C.; Karawajew, L.; Schott, G.; Schrappe, M.; Harbott, J.; Riehm, H.; Ludwig, W.D. Immunophenotype and Clinical Characteristics of CD45-Negative and CD45-Positive Childhood Acute Lymphoblastic Leukemia. Ann. Hematol. 1998, 77, 107–114. [Google Scholar] [CrossRef]
  117. Porcu, M.; Kleppe, M.; Gianfelici, V.; Geerdens, E.; De Keersmaecker, K.; Tartaglia, M.; Foà, R.; Soulier, J.; Cauwelier, B.; Uyttebroeck, A.; et al. Mutation of the Receptor Tyrosine Phosphatase PTPRC (CD45) in T-Cell Acute Lymphoblastic Leukemia. Blood 2012, 119, 4476–4479. [Google Scholar] [CrossRef]
  118. Tremblay, C.S.; Brown, F.C.; Collett, M.; Saw, J.; Chiu, S.K.; Sonderegger, S.E.; Lucas, S.E.; Alserihi, R.; Chau, N.; Toribio, M.L.; et al. Loss-of-Function Mutations of Dynamin 2 Promote T-ALL by Enhancing IL-7 Signalling. Leukemia 2016, 30, 1993–2001. [Google Scholar] [CrossRef] [PubMed]
  119. Brown, F.C.; Collett, M.; Tremblay, C.S.; Rank, G.; De Camilli, P.; Booth, C.J.; Bitoun, M.; Robinson, P.J.; Kile, B.T.; Jane, S.M.; et al. Loss of Dynamin 2 GTPase Function Results in Microcytic Anaemia. Br. J. Haematol. 2017, 178, 616–628. [Google Scholar] [CrossRef] [PubMed]
  120. Ge, Z.; Li, M.; Zhao, G.; Xiao, L.; Gu, Y.; Zhou, X.; Yu, M.D.; Li, J.; Dovat, S.; Song, C. Novel Dynamin 2 Mutations in Adult T-Cell Acute Ymphoblastic Leukemia. Oncol. Lett. 2016, 12, 2746–2751. [Google Scholar] [CrossRef] [PubMed]
  121. Russell, L.J.; Capasso, M.; Vater, I.; Akasaka, T.; Bernard, O.A.; Calasanz, M.J.; Chandrasekaran, T.; Chapiro, E.; Gesk, S.; Griffiths, M.; et al. Deregulated Expression of Cytokine Receptor Gene, CRLF2, Is Involved in Lymphoid Transformation in B-Cell Precursor Acute Lymphoblastic Leukemia. Blood 2009, 114, 2688–2698. [Google Scholar] [CrossRef]
  122. Harvey, R.C.; Mullighan, C.G.; Chen, I.M.; Wharton, W.; Mikhail, F.M.; Carroll, A.J.; Kang, H.; Liu, W.; Dobbin, K.K.; Smith, M.A.; et al. Rearrangement of CRLF2 Is Associated with Mutation of JAK Kinases, Alteration of IKZF1, Hispanic/Latino Ethnicity, and a Poor Outcome in Pediatric B-Progenitor Acute Lymphoblastic Leukemia. Blood 2010, 115, 5312–5321. [Google Scholar] [CrossRef] [PubMed]
  123. Yoda, A.; Yoda, Y.; Chiaretti, S.; Bar-Natan, M.; Mani, K.; Rodig, S.J.; West, N.; Xiao, Y.; Brown, J.R.; Mitsiades, C.; et al. Functional Screening Identifies CRLF2 in Precursor B-Cell Acute Lymphoblastic Leukemia. Proc. Natl. Acad. Sci. USA 2010, 107, 252–257. [Google Scholar] [CrossRef] [PubMed]
  124. Hertzberg, L.; Vendramini, E.; Ganmore, I.; Cazzaniga, G.; Schmitz, M.; Chalker, J.; Shiloh, R.; Iacobucci, I.; Shochat, C.; Zeligson, S.; et al. Down Syndrome Acute Lymphoblastic Leukemia, a Highly Heterogeneous Disease in Which Aberrant Expression of CRLF2 Is Associated with Mutated JAK2: A Report from the International BFM Study Group. Blood 2010, 115, 1006–1017. [Google Scholar] [CrossRef] [PubMed]
  125. Mullighan, C.G.; Collins-Underwood, J.R.; Phillips, L.A.A.; Loudin, M.G.; Liu, W.; Zhang, J.; Ma, J.; Coustan-Smith, E.; Harvey, R.C.; Willman, C.L.; et al. Rearrangement of CRLF2 in B-Progenitor-and Down Syndrome-Associated Acute Lymphoblastic Leukemia. Nat. Genet. 2009, 41, 1243–1246. [Google Scholar] [CrossRef] [PubMed]
  126. Chapiro, E.; Russell, L.; Lainey, E.; Kaltenbach, S.; Ragu, C.; Della-Valle, V.; Hanssens, K.; MacIntyre, E.A.; Radford-Weiss, I.; Delabesse, E.; et al. Activating Mutation in the TSLPR Gene in B-Cell Precursor Lymphoblastic Leukemia. Leukemia 2010, 24, 642–645. [Google Scholar] [CrossRef] [PubMed]
  127. Tal, N.; Shochat, C.; Geron, I.; Bercovich, D.; Izraeli, S. Interleukin 7 and Thymic Stromal Lymphopoietin: From Immunity to Leukemia. Cell. Mol. Life Sci. 2014, 71, 365–378. [Google Scholar] [CrossRef]
  128. Van Bodegom, D.; Zhong, J.; Kopp, N.; Dutta, C.; Kim, M.S.; Bird, L.; Weigert, O.; Tyner, J.; Pandey, A.; Yoda, A.; et al. Differences in Signaling through the B-Cell Leukemia Oncoprotein CRLF2 in Response to TSLP and through Mutant JAK2. Blood 2012, 120, 2853–2863. [Google Scholar] [CrossRef]
  129. Schluns, K.S.; Kieper, W.C.; Jameson, S.C.; Lefrançois, L. Interleukin-7 Mediates the Homeostasis of Naïve and Memory CD8 T Cells in Vivo. Nat. Immunol. 2000, 1, 426–432. [Google Scholar] [CrossRef]
  130. Dalloul, A.; Laroche, L.; Bagot, M.; Djavad Mossalayi, M.; Fourcade, C.; Thacker, D.J.; Hogge, D.E.; Merle-Béral, H.; Debré, P.; Schmitt, C. Interleukin-7 Is a Growth Factor for Sézary Lymphoma Cells. J. Clin. Investig. 1992, 90, 1054–1060. [Google Scholar] [CrossRef]
  131. Digel, W.; Schmid, M.; Heil, G.; Conrad, P.; Gillis, S.; Porzsolt, F. Human Interleukin-7 Induces Proliferation of Neoplastic Cells from Chronic Lymphocytic Leukemia and Acute Leukemias. Blood 1991, 78, 753–759. [Google Scholar] [CrossRef]
  132. Cattaruzza, L.; Gloghini, A.; Olivo, K.; Di Francia, R.; Lorenzon, D.; De Filippi, R.; Carbone, A.; Colombatti, A.; Pinto, A.; Aldinucci, D. Functional Coexpression of Interleukin (IL)-7 and Its Receptor (IL-7R) on Hodgkin and Reed-Sternberg Cells: Involvement of IL-7 in Tumor Cell Growth and Microenvironmental Interactions of Hodgkin’s Lymphoma. Int. J. Cancer 2009, 125, 1092–1101. [Google Scholar] [CrossRef]
  133. Waldmann, T.A.; Chen, J. Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy. Annu. Rev. Immunol. 2017, 35, 533–550. [Google Scholar] [CrossRef]
  134. Crescenzo, R.; Abate, F.; Lasorsa, E.; Tabbo’, F.; Gaudiano, M.; Chiesa, N.; Di Giacomo, F.; Spaccarotella, E.; Barbarossa, L.; Ercole, E.; et al. Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma. Cancer Cell 2015, 27, 516–532. [Google Scholar] [CrossRef] [PubMed]
  135. Koo, G.C.; Tan, S.Y.; Tang, T.; Poon, S.L.; Allen, G.E.; Tan, L.; Chong, S.C.; Ong, W.S.; Tay, K.; Tao, M.; et al. Janus Kinase 3-Activating Mutations Identifi Ed in Natural Killer/T-Cell Lymphoma. Cancer Discov. 2012, 2, 591–597. [Google Scholar] [CrossRef] [PubMed]
  136. Bouchekioua, A.; Scourzic, L.; De Wever, O.; Zhang, Y.; Cervera, P.; Aline-Fardin, A.; Mercher, T.; Gaulard, P.; Nyga, R.; Jeziorowska, D.; et al. JAK3 Deregulation by Activating Mutations Confers Invasive Growth Advantage in Extranodal Nasal-Type Natural Killer Cell Lymphoma. Leukemia 2014, 28, 338–348. [Google Scholar] [CrossRef] [PubMed]
  137. Rajala, H.L.M.; Porkka, K.; MacIejewski, J.P.; Loughran, T.P.; Mustjoki, S. Uncovering the Pathogenesis of Large Granular Lymphocytic Leukemia-Novel STAT3 and STAT5b Mutations. Ann. Med. 2014, 46, 114–122. [Google Scholar] [CrossRef]
  138. Küçük, C.; Jiang, B.; Hu, X.; Zhang, W.; Chan, J.K.C.; Xiao, W.; Lack, N.; Alkan, C.; Williams, J.C.; Avery, K.N.; et al. Activating Mutations of STAT5B and STAT3 in Lymphomas Derived from Γδ-T or NK Cells. Nat. Commun. 2015, 6. [Google Scholar] [CrossRef]
  139. Kleppe, M.; Tousseyn, T.; Geissinger, E.; Atak, Z.K.; Aerts, S.; Rosenwald, A.; Wlodarska, I.; Cools, J. Mutation Analysis of the Tyrosine Phosphatase PTPN2 in Hodgkin’s Lymphoma and T-Cell Non-Hodgkin’s Lymphoma. Haematologica 2011, 96, 1723–1727. [Google Scholar] [CrossRef]
  140. Cramer, S.D.; Aplan, P.D.; Durum, S.K. Therapeutic Targeting of IL-7Rα Signaling Pathways in ALL Treatment. Blood 2016, 128, 473–478. [Google Scholar] [CrossRef]
  141. Alsadeq, A.; Lenk, L.; Vadakumchery, A.; Cousins, A.; Vokuhl, C.; Khadour, A.; Vogiatzi, F.; Seyfried, F.; Meyer, L.H.; Cario, G.; et al. IL7R Is Associated with CNS Infiltration and Relapse in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. Blood 2018, 132, 1614–1617. [Google Scholar] [CrossRef]
  142. Yasunaga, M.; Manabe, S.; Matsumura, Y. Immunoregulation by IL-7R-Targeting Antibody-Drug Conjugates: Overcoming Steroid-Resistance in Cancer and Autoimmune Disease. Sci. Rep. 2017, 7, 1–14. [Google Scholar] [CrossRef] [PubMed]
  143. Hixon, J.A.; Andrews, C.; Kashi, L.; Kohnhorst, C.L.; Senkevitch, E.; Czarra, K.; Barata, J.T.; Li, W.; Schneider, J.P.; Walsh, S.T.R.; et al. New Anti-IL-7Rα Monoclonal Antibodies Show Efficacy against T Cell Acute Lymphoblastic Leukemia in Pre-Clinical Models. Leukemia 2020, 34, 35–49. [Google Scholar] [CrossRef]
  144. Akkapeddi, P.; Fragoso, R.; Hixon, J.A.; Ramalho, A.S.; Oliveira, M.L.; Carvalho, T.; Gloger, A.; Matasci, M.; Corzana, F.; Durum, S.K.; et al. A Fully Human Anti-IL-7Rα Antibody Promotes Antitumor Activity against T-Cell Acute Lymphoblastic Leukemia. Leukemia 2019, 33, 2155–2168. [Google Scholar] [CrossRef] [PubMed]
  145. Mansour, M.R.; Reed, C.; Eisenberg, A.R.; Tseng, J.C.; Twizere, J.C.; Daakour, S.; Yoda, A.; Rodig, S.J.; Tal, N.; Shochat, C.; et al. Targeting Oncogenic Interleukin-7 Receptor Signalling with N-Acetylcysteine in T Cell Acute Lymphoblastic Leukaemia. Br. J. Haematol. 2015, 168, 230–238. [Google Scholar] [CrossRef] [PubMed]
  146. Delgado-Martin, C.; Meyer, L.K.; Huang, B.J.; Shimano, K.A.; Zinter, M.S.; Nguyen, J.V.; Smith, G.A.; Taunton, J.; Winter, S.S.; Roderick, J.R.; et al. JAK/STAT Pathway Inhibition Overcomes IL7-Induced Glucocorticoid Resistance in a Subset of Human T-Cell Acute Lymphoblastic Leukemias. Leukemia 2017, 31, 2568–2576. [Google Scholar] [CrossRef]
  147. Degryse, S.; de Bock, C.E.; Demeyer, S.; Govaerts, I.; Bornschein, S.; Verbeke, D.; Jacobs, K.; Binos, S.; Skerrett-Byrne, D.A.; Murray, H.C.; et al. Mutant JAK3 Phosphoproteomic Profiling Predicts Synergism between JAK3 Inhibitors and MEK/BCL2 Inhibitors for the Treatment of T-Cell Acute Lymphoblastic Leukemia. Leukemia 2018, 32, 788–800. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Schematic representation of the IL-7R-JAK-STAT signaling pathway. The IL-7R-JAK-STAT signaling pathway is activated when interleukin-7 (IL-7) binds to the IL-7 receptor (IL-7R), which consists of IL-7Ralpha (IL-7Rα) and the common gamma chain (γc), resulting in the phosphorylation and thus activation of Janus kinase 1 (JAK1) and JAK3. Activated JAK proteins phosphorylate signal transducer and activator of transcription 5 (STAT5), and phosphorylated STAT5 homodimerizes and translocates to the nucleus where it regulates the expression of STAT5 target genes, such as BCL2, CISH, MYC, OSM and PIM1. Negative regulators of the pathway include the protein tyrosine phosphatases (PTP) non-receptor type 2 (PTPN2) and receptor type C (PTPRC, also known as CD45), as well as the large GTPase dynamin 2 (DNM2) which plays a role in the clathrin-dependent endocytosis of IL-7R.
Figure 1. Schematic representation of the IL-7R-JAK-STAT signaling pathway. The IL-7R-JAK-STAT signaling pathway is activated when interleukin-7 (IL-7) binds to the IL-7 receptor (IL-7R), which consists of IL-7Ralpha (IL-7Rα) and the common gamma chain (γc), resulting in the phosphorylation and thus activation of Janus kinase 1 (JAK1) and JAK3. Activated JAK proteins phosphorylate signal transducer and activator of transcription 5 (STAT5), and phosphorylated STAT5 homodimerizes and translocates to the nucleus where it regulates the expression of STAT5 target genes, such as BCL2, CISH, MYC, OSM and PIM1. Negative regulators of the pathway include the protein tyrosine phosphatases (PTP) non-receptor type 2 (PTPN2) and receptor type C (PTPRC, also known as CD45), as well as the large GTPase dynamin 2 (DNM2) which plays a role in the clathrin-dependent endocytosis of IL-7R.
Pharmaceuticals 14 00443 g001
Figure 2. Schematic representation of the CRLF2-JAK-STAT signaling pathway. In addition to the common gamma chain, interleukin-7 receptor alpha (IL-7Rα) can form heterodimers with cytokine receptor-like factor 2 (CRLF2), thereby creating the receptor for thymic stromal lymphopoietin (TSLP). Whereas IL-7-induced signaling activates signal transducer and activator of transcription 5 (STAT5) via the phosphorylation of Janus kinase 1 (JAK1) and JAK3, the binding of TSLP to the TSLP receptor results in STAT5 activation via the phosphorylation of JAK1 and JAK2.
Figure 2. Schematic representation of the CRLF2-JAK-STAT signaling pathway. In addition to the common gamma chain, interleukin-7 receptor alpha (IL-7Rα) can form heterodimers with cytokine receptor-like factor 2 (CRLF2), thereby creating the receptor for thymic stromal lymphopoietin (TSLP). Whereas IL-7-induced signaling activates signal transducer and activator of transcription 5 (STAT5) via the phosphorylation of Janus kinase 1 (JAK1) and JAK3, the binding of TSLP to the TSLP receptor results in STAT5 activation via the phosphorylation of JAK1 and JAK2.
Pharmaceuticals 14 00443 g002
Figure 3. Schematic representation of components of the IL-7R-JAK-STAT and CRLF2-JAK-STAT signaling pathways and their main protein domains. Interleukin-7 receptor alpha (IL-7Rα): extracellular domain with fibronectin type III-like domains DN1 and DN2 and four paired cysteine residues (C) and WSxWS motif, transmembrane domain, intracellular domain with four-point-one protein, ezrin, radixin, moesin (FERM) domain, BOX1 domain and three tyrosine residues (Y); Janus kinase 1 (JAK1): FERM domain, Src homology-2 (SH2) domain, pseudokinase domain, kinase domain; JAK3: FERM domain, SH2 domain, pseudokinase domain, kinase domain; signal transducer and activator of transcription 5B (STAT5B): N-terminal domain, coiled–coil domain, DNA binding domain, linker domain, SH2 domain, tyrosine residue Y694 (Y), transactivation domain; cytokine receptor-like factor 2 (CRLF2): extracellular domain with fibronectin type III-like domains DN1 and DN2 and only three cysteine residues (C) and WSxWS motif, transmembrane domain, intracellular domain with FERM domain, BOX1 domain and only one tyrosine residue; JAK2: FERM domain, SH2 domain, pseudokinase domain, kinase domain; protein tyrosine phosphatase non-receptor type 2 (PTPN2): catalytic domain, DNA binding domain, nuclear localization signal (NLS) or ER targeting sequence (ETS); dynamin 2 (DNM2): GTPase domain, middle domain, plekstrin homology domain, GTPase effector domain, proline-rich domain. Mutational hotspots are shown by dotted lines and the most frequently occurring genetic alterations are indicated.
Figure 3. Schematic representation of components of the IL-7R-JAK-STAT and CRLF2-JAK-STAT signaling pathways and their main protein domains. Interleukin-7 receptor alpha (IL-7Rα): extracellular domain with fibronectin type III-like domains DN1 and DN2 and four paired cysteine residues (C) and WSxWS motif, transmembrane domain, intracellular domain with four-point-one protein, ezrin, radixin, moesin (FERM) domain, BOX1 domain and three tyrosine residues (Y); Janus kinase 1 (JAK1): FERM domain, Src homology-2 (SH2) domain, pseudokinase domain, kinase domain; JAK3: FERM domain, SH2 domain, pseudokinase domain, kinase domain; signal transducer and activator of transcription 5B (STAT5B): N-terminal domain, coiled–coil domain, DNA binding domain, linker domain, SH2 domain, tyrosine residue Y694 (Y), transactivation domain; cytokine receptor-like factor 2 (CRLF2): extracellular domain with fibronectin type III-like domains DN1 and DN2 and only three cysteine residues (C) and WSxWS motif, transmembrane domain, intracellular domain with FERM domain, BOX1 domain and only one tyrosine residue; JAK2: FERM domain, SH2 domain, pseudokinase domain, kinase domain; protein tyrosine phosphatase non-receptor type 2 (PTPN2): catalytic domain, DNA binding domain, nuclear localization signal (NLS) or ER targeting sequence (ETS); dynamin 2 (DNM2): GTPase domain, middle domain, plekstrin homology domain, GTPase effector domain, proline-rich domain. Mutational hotspots are shown by dotted lines and the most frequently occurring genetic alterations are indicated.
Pharmaceuticals 14 00443 g003
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop