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Review

NKL-Code in Normal and Aberrant Hematopoiesis

by
Stefan Nagel
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany
Cancers 2021, 13(8), 1961; https://doi.org/10.3390/cancers13081961
Submission received: 12 March 2021 / Revised: 13 April 2021 / Accepted: 15 April 2021 / Published: 19 April 2021
(This article belongs to the Special Issue NKL Homeobox Genes in Normal and Aberrant Hematopoiesis)
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Abstract

:

Simple Summary

Gene codes represent expression patterns of closely related genes in particular tissues, organs or body parts. The NKL-code describes the activity of NKL homeobox genes in the hematopoietic system. NKL homeobox genes encode transcription factors controlling basic developmental processes. Therefore, aberrations of this code may contribute to deregulated hematopoiesis including leukemia and lymphoma. Normal and abnormal activities of NKL homeobox genes are described and mechanisms of (de)regulation, function, and diseases exemplified.

Abstract

We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.
Keywords:
NKL; homeobox; oncogene; T-ALL

1. Hematopoiesis

The hematopoietic system comprises all cells derived from hematopoietic stem cells (HSCs) (Figure 1). Novel comprehensive sequencing approaches have extended the characterization and derivation of progenitors and mature blood cells [1,2,3]. Hematopoietic stem and progenitor cells generate common myeloid and lymphoid progenitors (CMPs and CLPs), founders of the myeloid and lymphoid lineages, respectively. CLPs produce all types of lymphocytes comprising B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells (ILCs). Early B-cell development takes place in the bone marrow and begins with the CLP-derived B-cell progenitor (BCP). BCPs differentiate into naïve B-cells via the pro-B- and pre-B-cell stages. Naïve B-cells migrate from the bone marrow into lymph nodes, spleen and other lymphoid tissues to undergo final differentiation into memory B-cells and plasma cells via the stage of germinal center (GC) B-cells. In contrast, CLP-derived early T-cell progenitors (ETPs) migrate into the thymus to complete their differentiation via the double negative (DN) and double positive (DP) stages into CD4 and CD8 single-positive T-cells. CMPs produce all types of myeloid cells including erythrocytes and granulocytes which comprise eosinophils, neutrophils and basophils. Intermediate differentiation steps towards mature granulocytes include granulocyte macrophage progenitors (GMPs), early and late pro-myelocytes, and meta-myelocytes. Further myeloid cells are megakaryocytes and mast cells in addition to monocytes, which are able to differentiate into macrophages or dendritic cells. Unlike lymphocytes, all types of myeloid cells develop within the bone marrow.
The main regulatory steps of hematopoiesis operate at the transcriptional level by several transcription factors (TFs) identified as master genes for the development of early hematopoiesis, lymphopoiesis or myelopoiesis [3,4]. TAL1 and LYL1 are basic helix-turn-helix TF proteins and regulate vital steps in early and late hematopoiesis [5]. GATA factors are zinc-finger proteins that control hematopoietic stem cells (GATA2), erythropoiesis (GATA1), and NK- and T-cell development (GATA3) [6,7]. Additional TFs controlling specific processes in hematopoietic differentiation are EBF1 and PAX5 (development of B-cells), BCL11B (T-cells), NFIL3 (NK-cells), ID2 (ILCs), and SPI1/PU.1 (myeloid cells) [8,9,10,11,12]. These developmental regulators belong to different protein families, demonstrating that various types of TFs mediate the transcriptional control of hematopoiesis.

2. Classification of Homeobox Genes

Homeobox genes encode one of the largest groups of TFs in the human genome [13]. Generally, they regulate basic development and differentiation in both embryogenesis and the adult. These genes share the conserved homeobox which is 180 bp long and encodes the homeodomain at the protein level. This domain consists of 60 amino acid residues which form three helices, generating a specific 3D structure. The homeodomain performs specific interactions with DNA, chromatin, non-coding RNAs, and cooperating TFs, thus representing the core of their gene regulatory activities [14]. Specific DNA contacts are realized by helix 3 which fits into the major groove [15]. The remaining helices stabilize the domain structure and, together with flanking amino acid residues, allow additional DNA interactions (Figure 2).
From the systematic classification of all 235 human homeobox genes emerged a panel of eleven classes and several subclasses. The main classes are named antennapedia (ANTP) and paired box (PRD). Other classes identified are CERS, CUT, HNF, LIM, POU, PROS, SINE, TALE, and ZF. According to this system, NKL homeobox genes represent a subclass of the ANTP class and number 48 members in humans [16].
NK-like homeobox genes were first reported by Nirenberg and Kim (abbreviated as NK) in the fruit fly Drosophila, later summarized as NKL. In this developmental model organism, the NKL subclass members are arranged in a cluster consisting of six genes [17]. Additional orthologous genes were later identified, extending this group of genes. Comparative genome analyses revealed this clustering to be the ancient gene order which remains barely discernible in vertebrates [18]. Thus, human NKL homeobox genes show only relicts of a clustered arrangement while the HOX genes are still present in a clustered order in both fruit fly and humans.
NKL proteins share a conserved homeodomain which display the amino acid tyrosine at position 54 [19]. In addition, NKL homeodomain proteins contain a short and conserved sequence in their N-terminal region which has been termed engrailed-homology motif (EH1) [20]. This EH1 sequence mediates physical interactions with corepressors of the Groucho-family (transducin-like enhancer of split, TLE), thus transforming NKL homeodomain factors into transcriptional repressors [21] (Figure 2). Most NKL homeobox genes are involved in mesodermal development, possibly recapitulating their ancient functions, including the repression of alternative differentiation lineages [22,23]. Many NKL homeobox genes operate as master factors, further demonstrating the regulatory potential of these genes. For example, NKX2-5 controls the development of the spleen and heart, and NKX2-1 that of the lung and thyroid gland [24,25].

3. NKL-Code in Hematopoiesis

In several studies, we examined the physiological expression pattern of NKL homeobox genes in stem cells, progenitors and terminally differentiated blood cells across the whole hematopoietic spectrum. The lymphoid lineage was analyzed in four studies using public datasets of developing and mature T-cells, B-cells, NK-cells and ILCs [26,27,28,29]. Datasets covering the myeloid lineage were analyzed in a single study [30]. The accumulated results are summarized in Figure 3, showing NKL homeobox gene activities in distinct hematopoietic stages and cell types. Altogether, eleven NKL homeobox genes were identified, comprising DLX2, HHEX, HLX, HMX1, MSX1, NANOG, NKX2-3, NKX3-1, NKX6-3, TLX2 and VENTX. Their unique expression pattern has been termed NKL-code [26,27,28,29,30].
The most prominent among these genes are HHEX and HLX, active in HSCs, multiple progenitors, and various mature blood cells. The expression of NKX2-3 and NANOG is restricted to the earliest stages of hematopoiesis, including HSCs and lymphoid and myeloid primed progenitors (LMPs), respectively. NKX6-3 is just expressed in the B-cell lineage, TLX2 in the DN-stage of T-cell development, DLX2 in mature mast cells and monocytes, and HMX1 in the course of erythropoiesis. MSX1 is expressed in CLPs and in NK-cells. NKX3-1 shows a diverse expression pattern comprising undifferentiated HSCs and DN T-cells in addition to differentiated granulocytes and monocytes. The absence of NKL homeobox gene activity was reported for DP, CD4 and CD8 single-positive T-cells and for ILC1 and ILC2. Thus, in contrast to these lymphoid cell types, the remaining hematopoietic cells specifically express one or several members of the NKL homeobox gene subclass. Of note, some screenings for gene activities in these various hematopoietic cell types were conducted by expression profiling. The used gene chips do not contain the complete panel of known human genes and lacked eleven NKL homeobox genes (Table 1). However, analysis of RNA-seq data generated from various hematopoietic stem and progenitor cells confirmed the inactivity of these eleven genes in immature stages [31], supporting the integrity of the described NKL-code.
These findings were promoted by data reported for particular NKL homeobox genes and hematopoietic cell types. HLX and HHEX represent the first described non-HOX homeobox genes expressed in hematopoietic cells [32,33]. Expression analyses of both genes revealed activity in B- and myeloid cells while T-cells tested negative [32,34,35,36]. Moreover, the downregulation of HHEX was shown to be crucial for normal T-cell differentiation and its activity was absent in plasma cells [36]. Analysis of HHEX-knockout mice showed the disturbed development of all types of lymphocytes, demonstrating the importance of HHEX for lymphopoiesis [37]. Recently, a role of HHEX was shown in the development of memory B-cells, its expression in accordance with the NKL-code [27,38]. The forced expression of HLX in hematopoietic progenitors enhanced myeloid differentiation but arrested the development of B-cells at the pro-B-cell stage and of T-cells at the DP stage, highlighting the shutdown of its activity for lymphocyte maturation [34,39]. According to the NKL-code, VENTX is active in erythroid progenitors and is silenced at early stages of erythropoiesis [30]. Consistently, VENTX drives the expansion of erythroid cells and suppresses genes, promoting the terminal differentiation of erythrocytes [40].
Homeobox genes regulate basic processes in tissue and organ development. This potential in addition to specific activities of closely related homeobox genes has been referred by the annotation of codes. The HOX-code describes the ordered expression of the clustered HOX genes along the anterio–posterio axis of the developing hindbrain and of the embryonal pharynx [41,42]. The DLX-code addressed the expression pattern of DLX genes along the dorsal–ventral axis in the pharyngeal region of the embryo [43]. The identity of the developing placodes which generate different sensory organs is manifested by the expression of particular PAX genes and, accordingly, is termed the PAX-code [44]. Finally, the TALE-code defines a signature of TALE class homeobox genes in lymphopoiesis [45]. Thus, the NKL-code along with other homeobox gene codes serves to outline and understand developmental gene activities and their subordinate differentiation processes.

4. NKL Homeobox Genes in Non-Hematopoietic Tissues

In addition to hematopoiesis, NKL-code genes are also expressed in the development of other tissues or organs. HHEX (hematopoietically expressed homeobox gene) was one of the first homeobox genes identified in blood cells [33]. However, the same study reported that the activity of this gene is not restricted to the blood cell compartment—it was also detected in the lung and liver. Accordingly, HHEX is involved in differentiation processes of the lung and liver in addition to the thyroid gland and pancreas development [46]. Interestingly, the other basic hematopoietic NKL homeobox master gene, namely HLX, is also involved in the development of the lung and liver, in addition to the gut [47,48].
NANOG was first identified as a prominent stem cell factor in embryonic stem cells and plays an important role in the generation of induced pluripotent stem cells (iPSC) [49,50,51]. Together with other stem cell factors, such as OCT4, SOX2, FOXD3 and KLF4, NANOG establishes a gene network to control stemness [52,53]. Neural crest cells are generated during vertebrate development at the neural plate border and differentiate into a plethora of cells and tissues. Therefore, these cells possess conspicuous stem cell potential [54]. NANOG regulates together with VENTX the development of migrating neural crest cells. Both genes represent an evolutionary innovation of vertebrates, establishing a multipotent progenitor state [55]. Recently, VENTX was identified as an essential gene in pluripotent stem cells [56], further supporting the stemness-mediating activity for these NKL homeobox genes.
MSX1 is also associated with neural crest development and expressed at the neural plate border, controlling the generation of neural crest cells [54]. In successive steps, MSX1 regulates the development of the craniofacial region and the central nervous system [57]. Additionally, MSX1 is a central player in odontogenesis. Accordingly, mutations in the MSX1 coding region are associated with craniofacial malformations and teeth abnormalities [58,59]. At all these sites, BMP-signaling mutually regulates MSX1 activity [60,61]. Interestingly, the ectopic expression of MSX1 in myotubes promotes the dedifferentiation of these immature muscle cells [62], demonstrating the developmental power of this NKL homeobox gene.
NKX3-1 plays a central role in prostate development. Accordingly, the downregulation or mutation of this gene is seen in prostate cancer, indicating tumor suppressor activity [63]. HMX1 regulates ear development. Patients with certain regulatory HMX1 mutations display malformations of the outer ear while DLX2 is expressed in, and plays a developmental role for, the inner ear [64,65]. Moreover, together with other DLX genes, DLX2 organizes the development of the pharyngeal region in the embryo [43].
Thus, although NKL homeobox genes control specific processes in differentiation, they are not restricted to one particular tissue or organ. Their activities are mostly connected with early developmental stages or the progenitor state. In mature cells, NKL homeobox genes may support the manifestation of a particular cell type. These observations may indicate that these differentiation factors perform their function by controlling basic lineage decisions and the context-dependent regulation of cell-type specific genes. Hence, the mutation or deregulation of these genes is connected with malformations, developmental disorders or hereditary diseases.

5. Deregulated NKL Homeobox Genes in Hematopoietic Malignancies

In cell and tissue differentiation, specific intermediate stages are distinguishable. In cancer, normal progression is disturbed and developmental arrest at particular immature stages is a dominant and widespread feature of malignant cells [66,67,68]. Thus, cancer fairly represents a developmental disease. Accordingly, the forced expression of NKL homeobox gene HLX in hematopoietic progenitors resulted in the developmental arrest of pro-B-cells [39]. This experiment was the first hint for the oncogenic potential of NKL homeobox genes in hematopoietic cells. Later, Ferrando and coworkers described the aberrant expression of the NKL homeobox gene TLX1 at the DP stage in T-cell acute lymphoid leukemia (T-ALL), indicating that this gene specifically promotes the developmental arrest of malignant thymocytes [69]. The strong correlation of aberrantly expressed NKL homeobox genes with particular stages of lymphoid differentiation highlights the developmental potency of these genes in hematopoietic tumors.
Table 1 summarizes deregulated NKL homeobox genes identified in hematopoietic malignancies. Accordingly, 35 aberrantly expressed genes of the 48 gene strong NKL homeobox gene subclass have been described in these cancers, demonstrating their ubiquity and oncogenic impact in the hematopoietic compartment. Indeed, despite their relatively recent discovery, NKL homeobox genes form the most substantial group of oncogenes in leukemia and lymphoma. With few exceptions, most deregulated NKL homeobox genes are expressed in both lymphoid and myeloid malignancies. The following account summarizes deregulating mechanisms and oncogenic functions of selected NKL homeobox genes hitherto described in hematopoietic tumors.
TLX1: In 1991, the investigation of chromosomal rearrangement t(10;14)(q24;q11) in T-ALL patients by the group of Stanley Korsmeyer demonstrated the juxtaposition of T-cell receptor gene TRD and T-cell leukemia homeobox 1 (TLX1, formerly HOX11) [70]. Since then, aberrantly activated TLX1 emerged as a hallmark oncogene for this malignancy, although TLX1 is expressed in merely 10% of pediatric and 30% of adult T-ALL patients [69]. Retrospectively, TLX1 was the first NKL homeobox gene reportedly deregulated in hematopoietic malignancies. Normally, TLX1 plays a fundamental role in early spleen development, though it is not expressed in hematopoietic cells [71]. It is believed that TLX1 may perform its oncogenic function by the reactivation of embryonal splenic activities.
TLX3: In 2001, the group of Roger Berger identified a novel cryptic translocation, t(5;14)(q35;q32), in T-ALL subsets. This aberration activates T-cell leukemia homeobox 3 (TLX3, formerly HOX11L2) by juxtaposition to the BCL11B locus and was detected in about 25% of pediatric and 5% of adult T-ALL patients [72]. Despite their high similarity, TLX1- and TLX3-rearranged T-ALL patients show different prognoses [73]. Functionally, T-cell differentiation factor BCL11B is downregulated by chromosomal juxtaposition with TLX3 or directly by TF TLX1 [74]. Furthermore, TLX1 and TLX3 interact with TF ETS1 in T-ALL cells, thereby blocking TCR-rearrangement and T-cell differentiation [75]. Another gene family member, TLX2 (HOX11L1), though physiologically expressed in T-cell progenitors, is only rarely deregulated in T-ALL [26].
NKX2-5: In 2003, we reported an alternative, cytogenetically identical t(5;14)(q35;q32) in two T-ALL cell lines which juxtaposes BCL11B with NK2 homeobox 5 (NKX2-5, formerly CSX1) [76]. This indicative finding helped us to uncover the wider oncogenic role of NKL homeobox genes in T-ALL, then comprising TLX1, TLX3 and NKX2-5. Today, 24 deregulated NKL homeobox genes are described in T-ALL [26,77]. However, NKX2-5 is rarely expressed in this malignancy [26,78]. Normally, NKX2-5 plays a key physiological role in the development of the spleen and heart [24,71]. Uniting its physiological and leukemic roles, myocyte-specific enhancer factor 2C (MEF2C) has been shown to serve as a target gene of NKX2-5 in both heart and leukemic T-cells [79,80]. MEF2C itself has, meanwhile, emerged as a major oncogene in T-ALL, alternatively activated by chromosomal deletion and translocation, or by other deregulated transcription factors [80,81,82].
NKX2-1: In T-ALL, chromosomal translocation t(7;14)(q34;q13) causes the aberrant activation of NK2 homeobox 1 (NKX2-1) [81]. NKX2-1, like NKX2-2 and NKX2-5, activates MEF2C in T-ALL [81]. In addition, NKX2-1 is aberrantly activated in diffuse large B-cell lymphoma (DLBCL) where it is deregulated by an altered chromatin configuration instead of a chromosomal rearrangement [83]. Thus, the same NKL homeobox gene is aberrantly activated by diverse mechanisms in different lymphoid malignancies. Normally, NKX2-1 plays a role in the development of the lung and thyroid gland but is absent from hematopoietic cells and tissues [25].
NKX3-1: NK3 homeobox 1 (NKX3-1, formerly BAPX2) is hematopoietically expressed in stem cells and T-cell progenitors [26]. In T-ALL, NKX3-1 is aberrantly activated by the TFs TAL1 and GATA3 [84]. In leukemic T-cells, NKX3-1 expression correlates with oncogenic TAL1 activity and additionally with the expression of homeobox gene SIX6 [85]. SIX6 is directly activated by NKX3-1 or alternatively by the closely related factor NKX3-2 (BAPX1) as described in both T-ALL patients and cell lines [86,87]. However, the leukemic role of SIX6 in T-ALL remains unclear.
MSX1: Muscle segment homeobox gene 1 (MSX1) is aberrantly expressed in several types of leukemia and lymphoma, including T-ALL, Hodgkin lymphoma (HL) and mantle cell lymphoma [26,88]. In the hematopoietic system, MSX1 is normally expressed in lymphoid progenitors and mature NK-cells, reflecting its contrasting roles as oncogene in T-ALL and tumor suppressor in NK-cell leukemia [28]. In T-ALL, the downregulated BMP-signaling pathway and upregulated chromatin-mediator AUTS2 have been reported as activating mechanisms for MSX1 [89,90]. MSX1 plays a major role in the generation and development of neural crest cells [54], supporting its role as lineage regulator in stem/progenitor cells.
HLX: H2.0-like homeobox (HLX) is overexpressed in several hematopoietic malignancies including HL, DLBCL and anaplastic large cell lymphoma (ALCL) [27,29]. Aberrant activation by STAT3 plays a dominant role in HLX expression in these tumor types. The requirement of the nuclear localization of STAT3 for HLX activation has been shown in HL cell line L-540 [91]. The role of the Epstein–Barr virus-mediated activation of STAT3 in HLX expression was analyzed in the DLBCL cell line DOHH-2 [92]. Finally, STAT3 represents a hallmark factor in ALCL [93]. Analyses of several ALCL cell lines revealed genomic gains at STAT3 and HLX loci and demonstrated a direct activating impact of STAT3 in HLX expression, highlighting HLX as important oncogene and STAT3-target in this malignancy [29].
NKX2-3: NK2 homeobox 3 (NKX2-3) is a member of the NKL-code and expressed in HSCs [26]. Its focused activity suggests a regulatory role in maintaining stemness and self-renewal. In splenic marginal zone lymphoma (SMZL) aberrant NKX2-3 expression is driven by chromosomal translocation t(10;14)(q24;q32) via juxtaposition to the IGH-locus [94].
NANOG: Like NKX2-3, NANOG belongs to the NKL-code and shows restricted activity in early stem and progenitor cells [26]. The aberrant expression of NANOG has been described for NKT-cell lymphoma, AML and MDS [30,95]. Using AML cell line NOMO-1 as a model, we revealed the NOTCH signaling pathway and TET2-mediated aberrant DNA-methylation in NANOG activation [30]. Micro-RNA host gene MIR17HG is a target of NANOG in both AML and neural stem cells, contributing to the oncogenic function of this homeobox gene [30,96].
DLX2: Distal-less homeobox 2 (DLX2) is physiologically expressed in mature myeloid cells including mast cells, monocytes and monocyte-derived dendritic cells [30]. DLX2 is located at chromosomal position 2q31 next to its paralogue gene DLX1, which is normally silent in hematopoietic cells. Aberrant expression has been reported for both DLX1 and DLX2 in T-ALL, AML and MDS patients, indicating divergent regulation in the malignant context [26,30]. In AML, oncogenic ERK-signaling drives the expression of both DLX1 and DLX2 [97].
HMX: The human genome contains three related HMX genes. HMX1 is located at chromosomal position 4p16 and expressed in early erythropoiesis while HMX2 and HMX3 are located side by side at 10q26, being silent in hematopoiesis [30]. However, HMX2 and HMX3 are aberrantly expressed in AML and the activity of HMX1 was detected in subsets of myelodysplastic syndrome (MDS) patients [30]. HMX2 and HMX3 show an absence of chromosomal rearrangements and are activated by IL7-signaling and via the mutation of two transcription factor-binding sites in an AML cell line (EOL-1). One mutation transforms an inhibitory NFkB-site into an activatory SP1-site while the other mutation generates an activating ETS-site [98]. Functional analyses revealed the inhibition of differentiation gene EPX and activation of the receptor HTR7 that drives oncogenic ERK-signaling [98]. Furthermore, HMX2 and HMX3 inhibit eosinophilic cell differentiation as shown by morphological changes in the AML cell line model [98].
Together, these examples show that deregulated NKL homeobox genes perform basic oncogenic functions in hematopoietic malignancies. NKL homeobox genes act as oncogenes and tumor suppressor genes in other tissues as well, such as NKX2-1 and NKX3-1 in lung and prostate carcinoma, respectively [63,99]. In leukemia and lymphoma, deregulating mechanisms include chromosomal translocation, chromatin modifications, mutations in TF binding sites, altered DNA-methylation, and aberrant activities of particular TFs and signaling pathways such as BMP, ERK, or NOTCH. Downstream effects of these genes are even more diverse, including the activation of specific TFs and micro RNAs, inhibitory interaction with cell type specific TFs, the deregulation of differentiation markers and signaling pathways, in addition to disturbed proliferation, apoptosis and differentiation. Notably, ectopically expressed NKL homeobox genes highlight the role of activated alternative developmental processes for this group of oncogenes. The NKL-code and its oncogenic violation discloses an underlying pathological principle and the list of oncogenic activities performed by deregulated NKL homeobox genes comprises all characteristics described for tumorigenesis.

6. Tumor Cell Lines as Models for Deregulated NKL Homeobox Genes

Cell lines are clonal cells which grow unlimited in culture. They are genomically stable, survive freezing and thawing, and are available from cell line banks. Tumor cell lines represent experimental models for that tumor type from which they were derived. Therefore, it is of fundamental importance to use authenticated and well characterized cell lines to be able to transfer cell line data to particular cancers. In the literature evaluated and systematically listed, hematopoietic cell lines have been described which meet these criteria and include the tumor types ALCL, AML, chronic myeloid leukemia, B-cell precursor ALL, double-hit B-cell lymphomas, HL, MDS, multiple myeloma, NK-cell leukemia, primary effusion lymphoma and primary mediastinal B-cell lymphoma [100,101,102,103,104,105,106,107,108,109,110,111,112]. Recently, we have generated exomes and transcriptomes for 100 leukemia/lymphoma cell lines, providing comparative sequence data for a large panel of hematopoietic tumor entities [113]. These data may help to identify novel genes involved in the pathogenesis of particular tumor types.
Deregulated NKL homeobox genes were usually first ascertained in patients and investigated experimentally in cell lines to reveal mechanisms of deregulation and downstream activities. Table 2 shows leukemia/lymphoma cell lines, their corresponding diseases and aberrant NKL homeobox gene activities to help identify models to study a particular type of cancer and/or gene of interest.
In summary, NKL homeobox genes are physiologically expressed in hematopoiesis in a unique and specific pattern which we have termed NKL-code. This code serves to identify and evaluate deregulated NKL homeobox genes in leukemia/lymphoma. Aberrant activities of these basic developmental regulators contribute to the pathogenesis of hematopoietic malignancies. The knowledge of their pathophysiological activity may support the design of improved diagnostics and novel therapies in the future. Finally, validated cell lines represent suitable models to study the regulation and function of NKL homeobox genes in normal and malignant hematopoietic cells.

Funding

This research received no external funding.

Acknowledgments

The author wish to thank former colleagues and mentors Roderick A.F. MacLeod and Hans G. Drexler for their continuous support and inspiration and critical reading of the manuscript.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Uhlen, M.; Karlsson, M.J.; Zhong, W.; Tebani, A.; Pou, C.; Mikes, J.; Lakshmikanth, T.; Forsström, B.; Edfors, F.; Odeberg, J.; et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science 2019, 366, eaax9198. [Google Scholar] [CrossRef] [PubMed]
  2. Liggett, L.A.; Sankaran, V.G. Unraveling Hematopoiesis through the lens of genomics. Cell 2020, 182, 1384–1400. [Google Scholar] [CrossRef] [PubMed]
  3. Kucinski, I.; Wilson, N.K.; Hannah, R.; Kinston, S.J.; Cauchy, P.; Lenaerts, A.; Grosschedl, R.; Göttgens, B. Interactions between lineage-associated transcription factors govern haematopoietic progenitor states. EMBO J. 2020, 39, e104983. [Google Scholar] [CrossRef]
  4. Rothenberg, E.V. Transcriptional control of early T and B cell developmental choices. Annu. Rev. Immunol. 2014, 32, 283–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Souroullas, G.P.; Salmon, J.M.; Sablitzky, F.; Curtis, D.J.; Goodell, M.A. Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival. Cell Stem Cell 2009, 4, 180–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Crispino, J.D.; Horwitz, M.S. GATA factor mutations in hematologic disease. Blood 2017, 129, 2103–2110. [Google Scholar] [CrossRef]
  7. Van de Walle, I.; Dolens, A.C.; Durinck, K.; De Mulder, K.; Van Loocke, W.; Damle, S.; Waegemans, E.; De Medts, J.; Velghe, I.; De Smedt, M.; et al. GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate. Nat. Commun. 2016, 7, 11171. [Google Scholar] [CrossRef] [Green Version]
  8. Boller, S.; Grosschedl, R. The regulatory network of B-cell differentiation: A focused view of early B-cell factor 1 function. Immunol. Rev. 2014, 261, 102–115. [Google Scholar] [CrossRef]
  9. Avram, D.; Califano, D. The multifaceted roles of Bcl11b in thymic and peripheral T cells: Impact on immune diseases. J. Immunol. 2014, 193, 2059–2065. [Google Scholar] [CrossRef] [Green Version]
  10. Kostrzewski, T.; Borg, A.J.; Meng, Y.; Filipovic, I.; Male, V.; Wack, A.; DiMaggio, P.A.; Brady, H.J.M. Multiple levels of control determine how E4bp4/Nfil3 regulates NK cell development. J. Immunol. 2018, 200, 1370–1381. [Google Scholar] [CrossRef]
  11. Tanriver, Y.; Diefenbach, A. Transcription factors controlling development and function of innate lymphoid cells. Int. Immunol. 2014, 26, 119–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Liew, C.W.; Rand, K.D.; Simpson, R.J.; Yung, W.W.; Mansfield, R.E.; Crossley, M.; Proetorius-Ibba, M.; Nerlov, C.; Poulsen, F.M.; Mackay, J.P. Molecular analysis of the interaction between the hematopoietic master transcription factors GATA-1 and PU.1. J. Biol. Chem. 2006, 281, 28296–28306. [Google Scholar] [CrossRef] [Green Version]
  13. Vaquerizas, J.M.; Kummerfeld, S.K.; Teichmann, S.A.; Luscombe, N.M. A census of human transcription factors: Function, expression and evolution. Nat. Rev. Genet. 2009, 10, 252–263. [Google Scholar] [CrossRef]
  14. Bürglin, T.R.; Affolter, M. Homeodomain proteins: An update. Chromosoma 2016, 125, 497–521. [Google Scholar] [CrossRef] [Green Version]
  15. Gehring, W.J.; Müller, M.; Affolter, M.; Percival-Smith, A.; Billeter, M.; Qian, Y.Q.; Otting, G.; Wüthrich, K. The structure of the homeodomain and its functional implications. Trends Genet. 1990, 6, 323–329. [Google Scholar] [CrossRef]
  16. Holland, P.W.; Booth, H.A.; Bruford, E.A. Classification and nomenclature of all human homeobox genes. BMC Biol. 2007, 5, 47. [Google Scholar] [CrossRef] [Green Version]
  17. Kim, Y.; Nirenberg, M. Drosophila NK-homeobox genes. Proc. Natl. Acad. Sci. USA 1989, 86, 7716–7720. [Google Scholar] [CrossRef] [Green Version]
  18. Pollard, S.L.; Holland, P.W. Evidence for 14 homeobox gene clusters in human genome ancestry. Curr. Biol. 2000, 10, 1059–1062. [Google Scholar] [CrossRef] [Green Version]
  19. Harvey, R.P. NK-2 homeobox genes and heart development. Dev. Biol. 1996, 178, 203–216. [Google Scholar] [CrossRef] [Green Version]
  20. Smith, S.T.; Jaynes, J.B. A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development 1996, 122, 3141–3150. [Google Scholar]
  21. Jennings, B.H.; Ish-Horowicz, D. The Groucho/TLE/Grg family of transcriptional co-repressors. Genome Biol. 2008, 9, 205. [Google Scholar] [CrossRef] [PubMed]
  22. Garcia-Fernàndez, J. The genesis and evolution of homeobox gene clusters. Nat. Rev. Genet. 2005, 6, 881–892. [Google Scholar] [CrossRef]
  23. Jagla, K.; Bellard, M.; Frasch, M. A cluster of Drosophila homeobox genes involved in mesoderm differentiation programs. Bioessays 2001, 23, 125–133. [Google Scholar] [CrossRef]
  24. Lints, T.J.; Parsons, L.M.; Hartley, L.; Lyons, I.; Harvey, R.P. Nkx-2.5: A novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 1993, 119, 419–431. [Google Scholar]
  25. Lazzaro, D.; Price, M.; de Felice, M.; Di Lauro, R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 1991, 113, 1093–1104. [Google Scholar]
  26. Nagel, S.; Pommerenke, C.; Scherr, M.; Meyer, C.; Kaufmann, M.; Battmer, K.; MacLeod, R.A.; Drexler, H.G. NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia. PLoS ONE 2017, 12, e0171164. [Google Scholar] [CrossRef]
  27. Nagel, S.; MacLeod, R.A.F.; Meyer, C.; Kaufmann, M.; Drexler, H.G. NKL homeobox gene activities in B-cell development and lymphomas. PLoS ONE 2018, 13, e0205537. [Google Scholar] [CrossRef] [PubMed]
  28. Nagel, S.; Pommerenke, C.; Meyer, C.; Kaufmann, M.; MacLeod, R.A.F.; Drexler, H.G. NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia. Oncotarget 2017, 8, 66815–66832. [Google Scholar] [CrossRef] [Green Version]
  29. Nagel, S.; Pommerenke, C.; MacLeod, R.A.F.; Meyer, C.; Kaufmann, M.; Drexler, H.G. The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL). Oncotarget 2020, 11, 3208–3226. [Google Scholar] [CrossRef]
  30. Nagel, S.; Scherr, M.; MacLeod, R.A.F.; Pommerenke, C.; Koeppel, M.; Meyer, C.; Kaufmann, M.; Dallmann, I.; Drexler, H.G. NKL homeobox gene activities in normal and malignant myeloid cells. PLoS ONE 2019, 14, e0226212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Farlik, M.; Halbritter, F.; Müller, F.; Choudry, F.A.; Ebert, P.; Klughammer, J.; Farrow, S.; Santoro, A.; Ciaurro, V.; Mathur, A.; et al. DNA methylation dynamics of human hematopoietic stem cell differentiation. Cell Stem Cell 2016, 19, 808–822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Allen, J.D.; Lints, T.; Jenkins, N.A.; Copeland, N.G.; Strasser, A.; Harvey, R.P.; Adams, J.M. Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis. Genes Dev. 1991, 5, 509–520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Crompton, M.R.; Bartlett, T.J.; MacGregor, A.D.; Manfioletti, G.; Buratti, E.; Giancotti, V.; Goodwin, G.H. Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells. Nucleic Acids Res. 1992, 20, 5661–5667. [Google Scholar] [CrossRef] [Green Version]
  34. Bedford, F.K.; Ashworth, A.; Enver, T.; Wiedemann, L.M. HEX: A novel homeobox gene expressed during haematopoiesis and conserved between mouse and human. Nucleic Acids Res. 1993, 21, 1245–1249. [Google Scholar] [CrossRef] [Green Version]
  35. Manfioletti, G.; Gattei, V.; Buratti, E.; Rustighi, A.; De Iuliis, A.; Aldinucci, D.; Goodwin, G.H.; Pinto, A. Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells. Blood 1995, 85, 1237–1245. [Google Scholar] [CrossRef] [PubMed]
  36. Mack, D.L.; Leibowitz, D.S.; Cooper, S.; Ramsey, H.; Broxmeyer, H.E.; Hromas, R. Down-regulation of the myeloid homeobox protein Hex is essential for normal T-cell development. Immunology 2002, 107, 444–451. [Google Scholar] [CrossRef]
  37. Jackson, J.T.; Nasa, C.; Shi, W.; Huntington, N.D.; Bogue, C.W.; Alexander, W.S.; McCormack, M.P. A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis. Blood 2015, 125, 803–814. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Laidlaw, B.J.; Duan, L.; Xu, Y.; Vazquez, S.E.; Cyster, J.G. The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development. Nat. Immunol. 2020, 21, 1082–1093. [Google Scholar] [CrossRef]
  39. Allen, J.D.; Harris, A.W.; Bath, M.L.; Strasser, A.; Scollay, R.; Adams, J.M. Perturbed development of T and B cells in mice expressing an Hlx homeobox transgene. J. Immunol. 1995, 154, 1531–1542. [Google Scholar]
  40. Gentner, E.; Vegi, N.M.; Mulaw, M.A.; Mandal, T.; Bamezai, S.; Claus, R.; Tasdogan, A.; Quintanilla-Martinez, L.; Grunenberg, A.; Döhner, K.; et al. VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice. Oncotarget 2016, 7, 86889–86901. [Google Scholar] [CrossRef] [Green Version]
  41. Lewis, K.E. How do genes regulate simple behaviours? Understanding how different neurons in the vertebrate spinal cord are genetically specified. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2006, 361, 45–66. [Google Scholar] [CrossRef] [PubMed]
  42. Hunt, P.; Gulisano, M.; Cook, M.; Sham, M.H.; Faiella, A.; Wilkinson, D.; Boncinelli, E.; Krumlauf, R. A distinct Hox code for the branchial region of the vertebrate head. Nature 1991, 353, 861–864. [Google Scholar] [CrossRef]
  43. Depew, M.J.; Simpson, C.A.; Morasso, M.; Rubenstein, J.L. Reassessing the Dlx code: The genetic regulation of branchial arch skeletal pattern and development. J. Anat. 2005, 207, 501–561. [Google Scholar] [CrossRef] [PubMed]
  44. Streit, A. The cranial sensory nervous system: Specification of sensory progenitors and placodes. In StemBook; Harvard Stem Cell Institute: Cambridge, MA, USA, 2008. [Google Scholar]
  45. Nagel, S.; Pommerenke, C.; Meyer, C.; MacLeod, R.A.F.; Drexler, H.G. Establishment of the TALE-code reveals aberrantly activated homeobox gene PBX1 in Hodgkin lymphoma. PLoS ONE 2021, 16, e0246603. [Google Scholar] [CrossRef] [PubMed]
  46. Bogue, C.W.; Ganea, G.R.; Sturm, E.; Ianucci, R.; Jacobs, H.C. Hex expression suggests a role in the development and function of organs derived from foregut endoderm. Dev. Dyn. 2000, 219, 84–89. [Google Scholar] [CrossRef]
  47. Hentsch, B.; Lyons, I.; Li, R.; Hartley, L.; Lints, T.J.; Adams, J.M.; Harvey, R.P. Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. Genes Dev. 1996, 10, 70–79. [Google Scholar] [CrossRef] [Green Version]
  48. Lints, T.J.; Hartley, L.; Parsons, L.M.; Harvey, R.P. Mesoderm-specific expression of the divergent homeobox gene Hlx during murine embryogenesis. Dev. Dyn. 1996, 205, 457–470. [Google Scholar] [CrossRef]
  49. Chambers, I.; Colby, D.; Robertson, M.; Nichols, J.; Lee, S.; Tweedie, S.; Smith, A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003, 113, 643–655. [Google Scholar] [CrossRef] [Green Version]
  50. Mitsui, K.; Tokuzawa, Y.; Itoh, H.; Segawa, K.; Murakami, M.; Takahashi, K.; Maruyama, M.; Maeda, M.; Yamanaka, S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003, 113, 631–642. [Google Scholar] [CrossRef] [Green Version]
  51. Wernig, M.; Meissner, A.; Foreman, R.; Brambrink, T.; Ku, M.; Hochedlinger, K.; Bernstein, B.E.; Jaenisch, R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007, 448, 318–324. [Google Scholar] [CrossRef]
  52. Pan, G.; Thomson, J.A. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007, 17, 42–49. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, P.; Andrianakos, R.; Yang, Y.; Liu, C.; Lu, W. Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. J. Biol. Chem. 2010, 285, 9180–9189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Grocott, T.; Tambalo, M.; Streit, A. The peripheral sensory nervous system in the vertebrate head: A gene regulatory perspective. Dev. Biol. 2012, 370, 3–23. [Google Scholar] [CrossRef]
  55. Scerbo, P.; Monsoro-Burq, A.H. The vertebrate-specific VENTX/NANOG gene empowers neural crest with ectomesenchyme potential. Sci. Adv. 2020, 6, eaaz1469. [Google Scholar] [CrossRef] [PubMed]
  56. Mair, B.; Tomic, J.; Masud, S.N.; Tonge, P.; Weiss, A.; Usaj, M.; Tong, A.H.Y.; Kwan, J.J.; Brown, K.R.; Titus, E.; et al. Essential gene profiles for human pluripotent stem cells identify uncharacterized genes and substrate dependencies. Cell Rep. 2019, 27, 599–615. [Google Scholar] [CrossRef] [Green Version]
  57. Ramos, C.; Robert, B. msh/Msx gene family in neural development. Trends Genet. 2005, 21, 624–632. [Google Scholar] [CrossRef]
  58. Vastardis, H.; Karimbux, N.; Guthua, S.W.; Seidman, J.G.; Seidman, C.E. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat. Genet. 1996, 13, 417–421. [Google Scholar] [CrossRef]
  59. Liang, J.; Von den Hoff, J.; Lange, J.; Ren, Y.; Bian, Z.; Carels, C.E. MSX1 mutations and associated disease phenotypes: Genotype-phenotype relations. Eur. J. Hum. Genet. 2016, 24, 1663–1670. [Google Scholar] [CrossRef] [Green Version]
  60. Lan, Y.; Jia, S.; Jiang, R. Molecular patterning of the mammalian dentition. Semin. Cell Dev. Biol. 2014, 25–26, 61–70. [Google Scholar] [CrossRef] [Green Version]
  61. Zhang, Z.; Song, Y.; Zhao, X.; Zhang, X.; Fermin, C.; Chen, Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 2002, 129, 4135–4146. [Google Scholar]
  62. Odelberg, S.J.; Kollhoff, A.; Keating, M.T. Dedifferentiation of mammalian myotubes induced by msx1. Cell 2000, 103, 1099–1109. [Google Scholar] [CrossRef] [Green Version]
  63. Abate-Shen, C.; Shen, M.M.; Gelmann, E. Integrating differentiation and cancer: The Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Differentiation 2008, 76, 717–727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Alasti, F.; Van Camp, G. Genetics of microtia and associated syndromes. J. Med. Genet. 2009, 46, 361–369. [Google Scholar] [CrossRef]
  65. Brown, S.T.; Wang, J.; Groves, A.K. Dlx gene expression during chick inner ear development. J. Comp. Neurol. 2005, 483, 48–65. [Google Scholar] [CrossRef] [PubMed]
  66. O’Neil, J.; Look, A.T. Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 2007, 26, 6838–6849. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Eswaran, J.; Sinclair, P.; Heidenreich, O.; Irving, J.; Russell, L.J.; Hall, A.; Calado, D.P.; Harrison, C.J.; Vormoor, J. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia. Leukemia 2015, 29, 1623–1631. [Google Scholar] [CrossRef] [PubMed]
  68. Tomolonis, J.A.; Agarwal, S.; Shohet, J.M. Neuroblastoma pathogenesis: Deregulation of embryonic neural crest development. Cell Tissue Res. 2018, 372, 245–262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Ferrando, A.A.; Neuberg, D.S.; Staunton, J.; Loh, M.L.; Huard, C.; Raimondi, S.C.; Behm, F.G.; Pui, C.H.; Downing, J.R.; Gilliland, D.G.; et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002, 1, 75–87. [Google Scholar] [CrossRef] [Green Version]
  70. Hatano, M.; Roberts, C.W.; Minden, M.; Crist, W.M.; Korsmeyer, S.J. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 1991, 253, 79–82. [Google Scholar] [CrossRef]
  71. Brendolan, A.; Ferretti, E.; Salsi, V.; Moses, K.; Quaggin, S.; Blasi, F.; Cleary, M.L.; Selleri, L. A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny. Development 2005, 132, 3113–3126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Bernard, O.A.; Busson-LeConiat, M.; Ballerini, P.; Mauchauffé, M.; Della Valle, V.; Monni, R.; Nguyen Khac, F.; Mercher, T.; Penard-Lacronique, V.; Pasturaud, P.; et al. A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Leukemia 2001, 15, 1495–1504. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Meijerink, J.P. Genetic rearrangements in relation to immunophenotype and outcome in T-cell acute lymphoblastic leukaemia. Best Pract. Res. Clin. Haematol. 2010, 23, 307–318. [Google Scholar] [CrossRef] [PubMed]
  74. De Keersmaecker, K.; Real, P.J.; Gatta, G.D.; Palomero, T.; Sulis, M.L.; Tosello, V.; Van Vlierberghe, P.; Barnes, K.; Castillo, M.; Sole, X.; et al. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat. Med. 2010, 16, 1321–1327. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Dadi, S.; Le Noir, S.; Payet-Bornet, D.; Lhermitte, L.; Zacarias-Cabeza, J.; Bergeron, J.; Villarèse, P.; Vachez, E.; Dik, W.A.; Millien, C.; et al. TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression. Cancer Cell 2012, 21, 563–576. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Nagel, S.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 2003, 63, 5329–5334. [Google Scholar] [PubMed]
  77. Villarese, P.; Lours, C.; Trinquand, A.; Le Noir, S.; Belhocine, M.; Lhermitte, L.; Cieslak, A.; Tesio, M.; Petit, A.; LeLorch, M.; et al. TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome. Leukemia 2018, 32, 61–71. [Google Scholar] [CrossRef]
  78. Przybylski, G.K.; Dik, W.A.; Grabarczyk, P.; Wanzeck, J.; Chudobska, P.; Jankowski, K.; von Bergh, A.; van Dongen, J.J.; Schmidt, C.A.; Langerak, A.W. The effect of a novel recombination between the homeobox gene NKX2-5 and the TRD locus in T-cell acute lymphoblastic leukemia on activation of the NKX2-5 gene. Haematologica 2006, 91, 317–321. [Google Scholar]
  79. Skerjanc, I.S.; Petropoulos, H.; Ridgeway, A.G.; Wilton, S. Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other’s expression and initiate cardiomyogenesis in P19 cells. J. Biol. Chem. 1998, 273, 34904–34910. [Google Scholar] [CrossRef] [Green Version]
  80. Nagel, S.; Meyer, C.; Quentmeier, H.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines. Leukemia 2008, 22, 600–607. [Google Scholar] [CrossRef] [Green Version]
  81. Homminga, I.; Pieters, R.; Langerak, A.W.; de Rooi, J.J.; Stubbs, A.; Verstegen, M.; Vuerhard, M.; Buijs-Gladdines, J.; Kooi, C.; Klous, P.; et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell 2011, 19, 484–497. [Google Scholar] [CrossRef]
  82. Nagel, S.; Venturini, L.; Meyer, C.; Kaufmann, M.; Scherr, M.; Drexler, H.G.; Macleod, R.A. Transcriptional deregulation of oncogenic myocyte enhancer factor 2C in T-cell acute lymphoblastic leukemia. Leuk. Lymphoma 2011, 52, 290–297. [Google Scholar] [CrossRef] [PubMed]
  83. Nagel, S.; Ehrentraut, S.; Tomasch, J.; Quentmeier, H.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications. PLoS ONE 2013, 8, e61447. [Google Scholar] [CrossRef]
  84. Kusy, S.; Gerby, B.; Goardon, N.; Gault, N.; Ferri, F.; Gérard, D.; Armstrong, F.; Ballerini, P.; Cayuela, J.M.; Baruchel, A.; et al. NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia. J. Exp. Med. 2010, 207, 2141–2156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Soulier, J.; Clappier, E.; Cayuela, J.M.; Regnault, A.; García-Peydró, M.; Dombret, H.; Baruchel, A.; Toribio, M.L.; Sigaux, F. HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 2005, 106, 274–286. [Google Scholar] [CrossRef]
  86. Nagel, S.; Ehrentraut, S.; Tomasch, J.; Lienenklaus, S.; Schneider, B.; Geffers, R.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL). PLoS ONE 2012, 7, e40747. [Google Scholar] [CrossRef] [Green Version]
  87. Nagel, S.; Meyer, C.; Kaufmann, M.; Zaborski, M.; MacLeod, R.A.F.; Drexler, H.G. Aberrant activity of NKL homeobox gene NKX3-2 in a T-ALL subset. PLoS ONE 2018, 13, e0197194. [Google Scholar] [CrossRef]
  88. Nagel, S.; Ehrentraut, S.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. Oncogenic deregulation of NKL homeobox gene MSX1 in mantle cell lymphoma. Leuk. Lymphoma 2014, 55, 1893–1903. [Google Scholar] [CrossRef]
  89. Nagel, S.; Ehrentraut, S.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. Repressed BMP signaling reactivates NKL homeobox gene MSX1 in a T-ALL subset. Leuk. Lymphoma 2015, 56, 480–491. [Google Scholar] [CrossRef]
  90. Nagel, S.; Pommerenke, C.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; MacLeod, R.A. Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia. Oncotarget 2016, 7, 45398–45413. [Google Scholar] [CrossRef] [Green Version]
  91. Nagel, S.; Pommerenke, C.; Meyer, C.; Kaufmann, M.; MacLeod, R.A.F.; Drexler, H.G. Aberrant expression of NKL homeobox gene HLX in Hodgkin lymphoma. Oncotarget 2018, 9, 14338–14353. [Google Scholar] [CrossRef] [Green Version]
  92. Nagel, S.; Uphoff, C.C.; Dirks, W.G.; Pommerenke, C.; Meyer, C.; Drexler, H.G. Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL. PLoS ONE 2019, 14, e0216898. [Google Scholar] [CrossRef] [PubMed]
  93. Crescenzo, R.; Abate, F.; Lasorsa, E.; Tabbo’, F.; Gaudiano, M.; Chiesa, N.; Di Giacomo, F.; Spaccarotella, E.; Barbarossa, L.; Ercole, E.; et al. T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 2015, 27, 516–532. [Google Scholar] [PubMed] [Green Version]
  94. Robles, E.F.; Mena-Varas, M.; Barrio, L.; Merino-Cortes, S.V.; Balogh, P.; Du, M.Q.; Akasaka, T.; Parker, A.; Roa, S.; Panizo, C.; et al. Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics. Nat. Commun. 2016, 7, 11889. [Google Scholar] [CrossRef]
  95. Nagel, S.; Pommerenke, C.; MacLeod, R.A.F.; Meyer, C.; Kaufmann, M.; Fähnrich, S.; Drexler, H.G. Deregulated expression of NKL homeobox genes in T-cell lymphomas. Oncotarget 2019, 10, 3227–3247. [Google Scholar] [CrossRef] [PubMed]
  96. Garg, N.; Po, A.; Miele, E.; Campese, A.F.; Begalli, F.; Silvano, M.; Infante, P.; Capalbo, C.; De Smaele, E.; Canettieri, G.; et al. microRNA-17-92 cluster is a direct Nanog target and controls neural stem cell through Trp53inp1. EMBO J. 2013, 32, 2819–2832. [Google Scholar] [CrossRef] [PubMed]
  97. Starkova, J.; Gadgil, S.; Qiu, Y.H.; Zhang, N.; Hermanova, I.; Kornblau, S.M.; Drabkin, H.A. Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling. Haematologica 2011, 96, 820–828. [Google Scholar] [CrossRef]
  98. Nagel, S.; Pommerenke, C.; Meyer, C.; MacLeod, R.A.F.; Drexler, H.G. Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia. PLoS ONE 2020, 15, e0240120. [Google Scholar] [CrossRef]
  99. Yamaguchi, T.; Hosono, Y.; Yanagisawa, K.; Takahashi, T. NKX2-1/TTF-1: An enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell 2013, 23, 718–723. [Google Scholar] [CrossRef] [Green Version]
  100. Drexler, H.G. Guide to Leukemia-Lymphoma Cell Lines, 2nd ed.; DSMZ: Braunschweig, Germany, 2010. [Google Scholar]
  101. Drexler, H.G.; MacLeod, R.A. Malignant hematopoietic cell lines: In vitro models for the study of anaplastic large-cell lymphoma. Leukemia 2004, 18, 1569–1571. [Google Scholar] [CrossRef]
  102. Drexler, H.G.; Matsuo, Y.; MacLeod, R.A. Malignant hematopoietic cell lines: In vitro models for the study of erythroleukemia. Leuk. Res. 2004, 28, 1243–1251. [Google Scholar] [CrossRef] [PubMed]
  103. Drexler, H.G.; Quentmeier, H.; MacLeod, R.A.; Uphoff, C.C.; Hu, Z.B. Leukemia cell lines: In vitro models for the study of acute promyelocytic leukemia. Leuk. Res. 1995, 19, 681–691. [Google Scholar] [CrossRef]
  104. Drexler, H.G. Leukemia cell lines: In vitro models for the study of chronic myeloid leukemia. Leuk. Res. 1994, 18, 919–927. [Google Scholar] [CrossRef]
  105. Matsuo, Y.; Drexler, H.G. Establishment and characterization of human B cell precursor-leukemia cell lines. Leuk. Res. 1998, 22, 567–579. [Google Scholar] [CrossRef]
  106. Drexler, H.G.; Eberth, S.; Nagel, S.; MacLeod, R.A. Malignant hematopoietic cell lines: In vitro models for double-hit B-cell lymphomas. Leuk. Lymphoma 2016, 57, 1015–1020. [Google Scholar] [CrossRef] [PubMed]
  107. Drexler, H.G.; Pommerenke, C.; Eberth, S.; Nagel, S. Hodgkin lymphoma cell lines: To separate the wheat from the chaff. Biol. Chem. 2018, 399, 511–523. [Google Scholar] [CrossRef] [PubMed]
  108. Drexler, H.G. Malignant hematopoietic cell lines: In vitro models for the study of myelodysplastic syndromes. Leuk. Res. 2000, 24, 109–115. [Google Scholar] [CrossRef]
  109. Drexler, H.G.; Matsuo, Y. Malignant hematopoietic cell lines: In vitro models for the study of multiple myeloma and plasma cell leukemia. Leuk. Res. 2000, 24, 681–703. [Google Scholar] [CrossRef]
  110. Drexler, H.G.; Matsuo, Y. Malignant hematopoietic cell lines: In vitro models for the study of natural killer cell leukemia-lymphoma. Leukemia 2000, 14, 777–782. [Google Scholar] [CrossRef] [Green Version]
  111. Carbone, A.; Cesarman, E.; Gloghini, A.; Drexler, H.G. Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma through its derived cell lines. AIDS 2010, 24, 479–490. [Google Scholar] [CrossRef] [Green Version]
  112. Drexler, H.G.; Ehrentraut, S.; Nagel, S.; Eberth, S.; MacLeod, R.A. Malignant hematopoietic cell lines: In vitro models for the study of primary mediastinal B-cell lymphomas. Leuk. Res. 2015, 39, 18–29. [Google Scholar] [CrossRef]
  113. Quentmeier, H.; Pommerenke, C.; Dirks, W.G.; Eberth, S.; Koeppel, M.; MacLeod, R.A.F.; Nagel, S.; Steube, K.; Uphoff, C.C.; Drexler, H.G. The LL-100 panel: 100 cell lines for blood cancer studies. Sci. Rep. 2019, 9, 8218. [Google Scholar] [CrossRef] [PubMed]
  114. Nagel, S.; Schneider, B.; Meyer, C.; Kaufmann, M.; Drexler, H.G.; Macleod, R.A. Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma. Leuk. Res. 2012, 36, 646–655. [Google Scholar] [CrossRef]
  115. Nagel, S.; MacLeod, R.A.F.; Pommerenke, C.; Meyer, C.; Kaufmann, M.; Drexler, H.G. NKL homeobox gene NKX2-2 is aberrantly expressed in Hodgkin lymphoma. Oncotarget 2018, 9, 37480–37496. [Google Scholar] [CrossRef]
  116. Nagel, S.; Scherr, M.; Kel, A.; Hornischer, K.; Crawford, G.E.; Kaufmann, M.; Meyer, C.; Drexler, H.G.; MacLeod, R.A. Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3’-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res. 2007, 67, 1461–1471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. MacLeod, R.A.; Nagel, S.; Kaufmann, M.; Janssen, J.W.; Drexler, H.G. Activation of HOX11L2 by juxtaposition with 3’-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). Genes Chromosomes Cancer 2003, 37, 84–91. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Schematic presentation of hematopoiesis. This diagram depicts the progenitors and terminally differentiated cells of hematopoiesis, comprising the myeloid (left) and lymphoid (right) lineage. The following abbreviations are used: BCP: B-cell progenitor, CILCP: common ILC progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, ETP: early T-cell progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and myeloid primed progenitor, NKP: NK-cell progenitor. Figure modified from www.pinterest.de.
Figure 1. Schematic presentation of hematopoiesis. This diagram depicts the progenitors and terminally differentiated cells of hematopoiesis, comprising the myeloid (left) and lymphoid (right) lineage. The following abbreviations are used: BCP: B-cell progenitor, CILCP: common ILC progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, ETP: early T-cell progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and myeloid primed progenitor, NKP: NK-cell progenitor. Figure modified from www.pinterest.de.
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Cancers 13 01961 g002 550
Figure 2. Schematic structure of NKL homeodomain proteins. N: N-terminal end; C: C-terminal end; EH1: conserved engrailed homology domain consisting of about 8 amino acid residues (shown in green); the conserved homeodomain consists of 60 amino acid residues which generate three helices (H1-3) and is shown in blue; the N- and C-terminal parts show no sequence conservation. The EH1 domain and the homeodomain interact with particular components of the gene regulatory machinery including corepressors of the TLE family and specific DNA sequences, respectively.
Figure 2. Schematic structure of NKL homeodomain proteins. N: N-terminal end; C: C-terminal end; EH1: conserved engrailed homology domain consisting of about 8 amino acid residues (shown in green); the conserved homeodomain consists of 60 amino acid residues which generate three helices (H1-3) and is shown in blue; the N- and C-terminal parts show no sequence conservation. The EH1 domain and the homeodomain interact with particular components of the gene regulatory machinery including corepressors of the TLE family and specific DNA sequences, respectively.
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Cancers 13 01961 g003 550
Figure 3. The NKL-code in hematopoiesis This diagram depicts activities of NKL homeobox genes during early hematopoiesis, in lymphopoiesis including the development of T-cells, B-cells, NK-cells and ILCs, and in myelopiesis. Each cell/stage is labelled with the accordingly expressed NKL homeobox genes. BCP: B-cell progenitor, CILP: common innate lymphoid progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, DC: dendritic cell, DN: double negative, DP: double positive, ETP: early T-cell progenitor, GC B-cell: germinal center B-cell, GMP: granulocytic-monocytic progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and myeloid primed progenitor, memo B-cell: memory B-cell, MEP: megakaryocyte-erythroid-progenitor. Of note, this code was generated analyzing expression profiling and RNA-seq data.
Figure 3. The NKL-code in hematopoiesis This diagram depicts activities of NKL homeobox genes during early hematopoiesis, in lymphopoiesis including the development of T-cells, B-cells, NK-cells and ILCs, and in myelopiesis. Each cell/stage is labelled with the accordingly expressed NKL homeobox genes. BCP: B-cell progenitor, CILP: common innate lymphoid progenitor, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, DC: dendritic cell, DN: double negative, DP: double positive, ETP: early T-cell progenitor, GC B-cell: germinal center B-cell, GMP: granulocytic-monocytic progenitor, HSC: hematopoietic stem cell, ILC(P): innate lymphoid cell (progenitor), LMP: lymphoid and myeloid primed progenitor, memo B-cell: memory B-cell, MEP: megakaryocyte-erythroid-progenitor. Of note, this code was generated analyzing expression profiling and RNA-seq data.
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Table
Table 1. Aberrantly expressed NKL homeobox genes in leukemia/lymphoma patients. This table lists all 48 NKL homeobox genes which are deregulated in defined lymphoid and myeloid malignancies (totally 35). NKL-code members are indicated by gray background, genes not represented on the analyzed expression arrays are indicated in blue letters. Lymphoid malignancies are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell lymphoma (HCL), Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), NKT-cell lymphoma (NKTL), peripheral T-cell lymphoma (PTCL), and T-cell acute lymphoid leukemia (T-ALL). B- and T-cell malignancies are indicated in orange. Myeloid malignancies comprise acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and are indicated in green.
Table 1. Aberrantly expressed NKL homeobox genes in leukemia/lymphoma patients. This table lists all 48 NKL homeobox genes which are deregulated in defined lymphoid and myeloid malignancies (totally 35). NKL-code members are indicated by gray background, genes not represented on the analyzed expression arrays are indicated in blue letters. Lymphoid malignancies are diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell lymphoma (HCL), Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), NKT-cell lymphoma (NKTL), peripheral T-cell lymphoma (PTCL), and T-cell acute lymphoid leukemia (T-ALL). B- and T-cell malignancies are indicated in orange. Myeloid malignancies comprise acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and are indicated in green.
DLBCLFLHCLHLMCLSMZLAITLALCLATLLHSTLNKTLPTCLT-ALLAMLMDS
BARHL1
BARHL2
BARX1
BARX2
BSX
DBX1
DBX2
DLX1
DLX2
DLX3
DLX4
DLX5
DLX6
EMX1
EMX2
EN1
EN2
HHEX
HLX
HMX1
HMX2
HMX3
LBX1
LBX2
MSX1
MSX2
NANOG
NKX1-1
NKX1-2
NKX2-1
NKX2-2
NKX2-3
NKX2-4
NKX2-5
NKX2-6
NKX2-8
NKX3-1
NKX3-2
NKX6-1
NKX6-2
NKX6-3
NOTO
TLX1
TLX2
TLX3
VAX1
VAX2
VENTX
48 (35)33265379661111241814
Table
Table 2. Aberrantly expressed NKL homeobox genes in leukemia/lymphoma cell lines. This table lists hematopoietic cell lines in which particular NKL homeobox genes are overexpressed. Additionally, the corresponding disease and potentially relevant information are given. NKL-code members are indicated by gray background, genes not represented on the analyzed expression array are indicated in blue.
Table 2. Aberrantly expressed NKL homeobox genes in leukemia/lymphoma cell lines. This table lists hematopoietic cell lines in which particular NKL homeobox genes are overexpressed. Additionally, the corresponding disease and potentially relevant information are given. NKL-code members are indicated by gray background, genes not represented on the analyzed expression array are indicated in blue.
GeneCell LineDiseaseRegulated byEffect, Target GenesReference
BARHL1
BARHL2
BARX1
BARX2RPMI-8226MM [113]
BSX
DBX1
DBX2
DLX1EOL-1AML [98]
DLX2EOL-1AMLERK-signaling [98]
HPB-ALLT-ALL [113]
DLX3
DLX4
DLX5NOMO-1AMLNANOG [30]
DLX6NOMO-1AMLNANOG [30]
EMX1
EMX2
EN1
EN2
HHEXCCRF-CEMT-ALL [113]
RPMI-8402T-ALL [113]
HLXL-540HLaberrant STAT3 activity [91]
DOHH-2DLBCLEBV-mediated STAT3 [92]
OCI-LY19DLBCL [113]
NU-DHL-1DLBCL [113]
SEMBCP-ALL [113]
DELALCLaberrant STAT3 activity [29]
KI-JKALCLaberrant STAT3 activity [29]
L-82ALCLaberrant STAT3 activity [29]
SR-786ALCLaberrant STAT3 activity [29]
SU-DHL-1ALCLaberrant STAT3 activity [29]
SUP-M2ALCLaberrant STAT3 activity [29]
HMX1
HMX2EOL-1AML inhibits EPX, activates HRT7 and ERK[98]
MOLM-13AML [98]
MV4-11AML [98]
697BCP-ALL [98]
REHBCP-ALL [98]
HMX3EOL-1AML inhibits EPX, activates HRT7 and ERK[98]
MOLM-13AML [98]
MV4-11AML [98]
SEMBCP-ALL [113]
LBX1
LBX2
MSX1L-1236HLsuppressed BMP-pathwaycofactor H1C, target ZHX2[114]
GRANTA-519MCL CCND1 in t(11;14)(q13;q32)[88]
JEKO-1MCL CCND1 in t(11;14)(q13;q32)[88]
REC-1MCL CCND1 in t(11;14)(q13;q32)[88]
LOUCYETP-ALL [89]
MSX2
NANOGNOMO-1AML NOTCH, CDK6, MIR17HG[30]
NKX1-1
NKX1-2
NKX2-1SU-DHL-5DLBCLKMT2A, H2B [83]
RPMI-8402T-ALL [113]
NKX2-2DEVHLIL17RB-signaling [115]
NKX2-3
NKX2-4
NKX2-5CCRF-CEMT-ALLt(5;14)(q35;q32)activates MEF2C[76,80]
PEERT-ALLt(5;14)(q35;q32)activates MEF2C[76,80]
NKX2-6
NKX2-8
NKX3-1JURKATT-ALLTAL1 and GATA3activates SIX6[84,86]
MOLT-4T-ALL [86]
PER-117T-ALL [86]
PF-392T-ALL [86]
RPMI-8402T-ALL [86]
OCI-LY9DLBCL [113]
NKX3-2CCRF-CEMT-ALLsuppressed BMP-pathwayactivates SIX6[87]
NKX6-1
NKX6-2
NKX6-3DOHH-2DLBCLrepressed by HLX and HHEX, activated by PAX5 and MYBinhibits PAX5 and MSX1[27]
NOTO
TLX1ALL-SILT-ALLt(10;14)(q24;q11)ETS1-interaction[70,75]
TLX2SUP-HD1HLactivated by PBX1activates TBX15[45]
TLX3DND-41T-ALLt(5;14)(q35;q32) [116]
HPB-ALLT-ALLt(5;14)(q35;q32) [117]
VAX1
VAX2
VENTXSEMBCP-ALL [113]
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Nagel, S. NKL-Code in Normal and Aberrant Hematopoiesis. Cancers 2021, 13, 1961. https://doi.org/10.3390/cancers13081961

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Nagel S. NKL-Code in Normal and Aberrant Hematopoiesis. Cancers. 2021; 13(8):1961. https://doi.org/10.3390/cancers13081961

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Nagel, Stefan. 2021. "NKL-Code in Normal and Aberrant Hematopoiesis" Cancers 13, no. 8: 1961. https://doi.org/10.3390/cancers13081961

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