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Protein Kinase in Leukemia

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 54675

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Dr. Jean-Max Pasquet

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Guest Editor

U1035 INSERM, University of Bordeaux, Bordeaux, France
Interests: oncogenic signaling; kinases; leukemia; targeted therapies; resistance; stem cells
Special Issues, Collections and Topics in MDPI journals

Dr. Paulo De Sepulveda

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Cancer Research Center of Marseille, CRCM, INSERM U1068, UMR7258 CNRS, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France
Interests: protein kinases; leukemia; signaling; membrane receptors; kinase inhibitors

Special Issue Information

Dear Colleagues,

Protein kinases are required to phosphorylate substrates on threonine, serine or tyrosine residues, allowing structural protein modification leading to enzyme activation or recruitments of signaling partners at docking sites, giving raise to signaling transduction pathways. About 500 human genes encode kinases. Kinase activity controls signaling pathways involved in many cellular processes, such as cell growth, proliferation, differentiation or metabolism. In hematopoiesis, many kinases play a key role at different steps of blood cell generation, and deregulation, through mutations, expression or location, often leads to malignancies. Among these, several chronic or acute leukemias are driven by deregulated kinases, for which recent decades have seen the development of targeted therapies. Although tyrosine phosphorylations represent only 0.1% of whole phosphorylation, deregulated tyrosine kinases are involved in a large number of oncogenic mechanisms.

Blocking kinase enzymatic activity has therefore become a quest for pharmaceutical companies. The paradigm of kinase targeting is remembered by the development of the first inhibitor FDA-approved in chronic myeloid leukemia (CML) treatment, imatinib.

Today, around 50 kinase inhibitors are FDA-approved, while at least 150 are being investigated in clinical trials.

Dr. Jean-Max Pasquet
Dr. Paulo De Sepulveda
Guest Editors

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Keywords

Leukemia
Kinase
Oncogenic Signaling
Targeted Therapies
Resistance

Published Papers (13 papers)

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Editorial

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2 pages, 182 KiB

Open AccessEditorial

Protein Kinases in Leukemias

by Paulo De Sepulveda and Jean-Max Pasquet

Cancers 2021, 13(11), 2747; https://doi.org/10.3390/cancers13112747 - 01 Jun 2021

Viewed by 1531

Abstract

Protein kinases (PK) make up around 2% of the human genome and their expression profile varies depending on the organ and tissue [...] Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

Research

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18 pages, 3475 KiB

Open AccessArticle

Combination of PKCδ Inhibition with Conventional TKI Treatment to Target CML Models

by Fabien Muselli, Lucas Mourgues, Rita Morcos, Nathalie Rochet, Marielle Nebout, Agnès Guerci-Bresler, Douglas V Faller, Robert M William, Rana Mhaidly, Els Verhoeyen, Laurence Legros, Jean-François Peyron and Didier Mary

Cancers 2021, 13(7), 1693; https://doi.org/10.3390/cancers13071693 - 02 Apr 2021

Cited by 3 | Viewed by 2183

Abstract

Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34⁺ and BCR-ABL-transduced healthy CD34⁺ cells as efficiently as any TKI while it did not affect differentiation of healthy CD34⁺ cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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22 pages, 4813 KiB

Open AccessArticle

Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

by Emilie Logie, Chandra S. Chirumamilla, Claudina Perez-Novo, Priyanka Shaw, Ken Declerck, Ajay Palagani, Savithri Rangarajan, Bart Cuypers, Nicolas De Neuter, Fazil Mobashar Hussain Urf Turabe, Navin Kumar Verma, Annemie Bogaerts, Kris Laukens, Fritz Offner, Pieter Van Vlierberghe, Xaveer Van Ostade and Wim Vanden Berghe

Cancers 2021, 13(7), 1618; https://doi.org/10.3390/cancers13071618 - 31 Mar 2021

Cited by 9 | Viewed by 4732

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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10 pages, 663 KiB

Open AccessArticle

Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group

by Joanna Zawitkowska, Monika Lejman, Marcin Płonowski, Joanna Bulsa, Tomasz Szczepański, Michał Romiszewski, Agnieszka Mizia-Malarz, Katarzyna Derwich, Grażyna Karolczyk, Tomasz Ociepa, Magdalena Ćwiklińska, Joanna Trelińska, Joanna Owoc-Lempach, Ninela Irga-Jaworska, Anna Małecka, Katarzyna Machnik, Justyna Urbańska-Rakus, Radosław Chaber, Jerzy Kowalczyk and Wojciech Młynarski

Cancers 2020, 12(12), 3751; https://doi.org/10.3390/cancers12123751 - 13 Dec 2020

Cited by 6 | Viewed by 2222

Abstract

The treatment of children with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is currently unsuccessful. The use of tyrosine kinase inhibitors (TKIs) combined with chemotherapy has modernized ALL Ph+ therapy and appears to improve clinical outcome. We report herein the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post-induction treatment of Philadelphia chromosome positive ALL) in 15 hemato-oncological centers in Poland between the years 2012 and 2019. The study group included 31 patients, aged 1–18 years, with newly diagnosed ALL Ph+. All patients received TKIs. Imatinib was used in 30 patients, and ponatinib was applied in one child due to T315I and M244V mutation. During therapy, imatinib was replaced with dasatinib in three children. The overall survival of children with ALL Ph+ treated according to the EsPhALL2010 protocol was 74.1% and event-free survival was 54.2% after five years. The cumulative death risk of the study group at five years was estimated at 25.9%, and its cumulative relapse risk was 30%. Our treatment outcomes are still disappointing compared to other reports. Improvements in supportive care and emphasis placed on the determination of minimal residual disease at successive time points, which will impact decisions on therapy, may be required. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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12 pages, 1132 KiB

Open AccessArticle

Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study

by Pierre-Yves Dumas, Sarah Bertoli, Emilie Bérard, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Thibaut Leguay, Harmony Leroy, Noémie Gadaud, Jean Baptiste Rieu, Jean-Philippe Vial, François Vergez, Nicolas Lechevalier, Isabelle Luquet, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Arnaud Pigneux and Christian Récher

Cancers 2020, 12(8), 2044; https://doi.org/10.3390/cancers12082044 - 24 Jul 2020

Cited by 7 | Viewed by 2669

Abstract

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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12 pages, 1165 KiB

Open AccessArticle

Cardiovascular Toxicity of Tyrosine Kinase Inhibitors Used in Chronic Myeloid Leukemia: An Analysis of the FDA Adverse Event Reporting System Database (FAERS)

by Santa Cirmi, Asmae El Abd, Louis Letinier, Michele Navarra and Francesco Salvo

Cancers 2020, 12(4), 826; https://doi.org/10.3390/cancers12040826 - 30 Mar 2020

Cited by 76 | Viewed by 6769

Abstract

Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukemia (CML), can be associated to cardiovascular (CV) adverse events (AEs). A case/non-case study was performed using AE reports registered in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to compare the risk of CV event reports related to TKIs indicated in the management of chronic myeloid leukemia (CML). Disproportionality of CV event-related TKIs was computed using the Reporting Odds Ratio (ROR) as a measure of potential risk increase. Nilotinib accounts for more than half of reported cases related to TKIs. Signal of Disproportionate Reporting (SDR) was found for cardiac failure, ischemic heart disease, cardiac arrhythmias, torsade de pointes/QT prolongation, hypertension, and pulmonary hypertension. Dasatinib and bosutinib were related to the highest disproportionality for cardiac failure. Nilotinib was associated with the highest SDR for ischemic heart disease, torsade de pointes/QT prolongation and cardiac arrhythmias. Only ponatinib was related to an SDR for hypertension, while dasatinib and imatinib were related to pulmonary hypertension. In the context of CML, TKIs have different safety profiles related to CV events, among which nilotinib seems particularly related to. These results claim for a revision of its CV safety profile mainly for the risk of torsade de pointes/QT prolongation. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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Review

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24 pages, 2222 KiB

Open AccessReview

Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia

by Christian Boni and Claudio Sorio

Cancers 2021, 13(10), 2311; https://doi.org/10.3390/cancers13102311 - 12 May 2021

Cited by 8 | Viewed by 3071

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by BCR-ABL1 oncogene expression. This dysregulated protein-tyrosine kinase (PTK) is known as the principal driver of the disease and is targeted by tyrosine kinase inhibitors (TKIs). Extensive documentation has elucidated how the transformation of malignant cells is characterized by multiple genetic/epigenetic changes leading to the loss of tumor-suppressor genes function or proto-oncogenes expression. The impairment of adequate levels of substrates phosphorylation, thus affecting the balance PTKs and protein phosphatases (PPs), represents a well-established cellular mechanism to escape from self-limiting signals. In this review, we focus our attention on the characterization of and interactions between PTKs and PPs, emphasizing their biological roles in disease expansion, the regulation of LSCs and TKI resistance. We decided to separate those PPs that have been validated in primary cell models or leukemia mouse models from those whose studies have been performed only in cell lines (and, thus, require validation), as there may be differences in the manner that the associated pathways are modified under these two conditions. This review summarizes the roles of diverse PPs, with hope that better knowledge of the interplay among phosphatases and kinases will eventually result in a better understanding of this disease and contribute to its eradication. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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15 pages, 1128 KiB

Open AccessReview

Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL

by Valerio Guarente and Paolo Sportoletti

Cancers 2021, 13(6), 1280; https://doi.org/10.3390/cancers13061280 - 13 Mar 2021

Cited by 14 | Viewed by 2878

Abstract

Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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32 pages, 1816 KiB

Open AccessEditor’s ChoiceReview

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

by Philipp von Hundelshausen and Wolfgang Siess

Cancers 2021, 13(5), 1103; https://doi.org/10.3390/cancers13051103 - 04 Mar 2021

Cited by 43 | Viewed by 6900

Abstract

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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20 pages, 2005 KiB

Open AccessReview

Janus Kinases in Leukemia

by Juuli Raivola, Teemu Haikarainen, Bobin George Abraham and Olli Silvennoinen

Cancers 2021, 13(4), 800; https://doi.org/10.3390/cancers13040800 - 14 Feb 2021

Cited by 33 | Viewed by 3779

Abstract

Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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21 pages, 1316 KiB

Open AccessEditor’s ChoiceReview

Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

by Kalpana K. Bhanumathy, Amrutha Balagopal, Frederick S. Vizeacoumar, Franco J. Vizeacoumar, Andrew Freywald and Vincenzo Giambra

Cancers 2021, 13(2), 184; https://doi.org/10.3390/cancers13020184 - 07 Jan 2021

Cited by 39 | Viewed by 8661

Abstract

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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26 pages, 2536 KiB

Open AccessReview

Dual Kinase Targeting in Leukemia

by Luca Mologni, Giovanni Marzaro, Sara Redaelli and Alfonso Zambon

Cancers 2021, 13(1), 119; https://doi.org/10.3390/cancers13010119 - 01 Jan 2021

Cited by 3 | Viewed by 4367

Abstract

Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and lymphoid tumors, giving details on preclinical studies as well as ongoing clinical trials. A brief overview of dual-targeting inhibitors (kinase/histone deacetylase (HDAC) and kinase/tubulin polymerization inhibitors) applied to leukemia is also given. Finally, the very recently developed Proteolysis Targeting Chimeras (PROTAC)-based kinase inhibitors are presented. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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18 pages, 2170 KiB

Open AccessReview

Novel Approaches to Target Mutant FLT3 Leukaemia

by Jörg P. Müller and Dirk Schmidt-Arras

Cancers 2020, 12(10), 2806; https://doi.org/10.3390/cancers12102806 - 29 Sep 2020

Cited by 13 | Viewed by 3296

Abstract

Fms-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinases (RTK) and is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene resulting in constitutively active FLT3 variants are frequently found in acute myeloid leukaemia (AML) patients and correlate with patient’s poor survival. Targeting FLT3 mutant leukaemic stem cells (LSC) is a key to efficient treatment of patients with relapsed/refractory AML. It is therefore essential to understand how LSC escape current therapies in order to develop novel therapeutic strategies. Here, we summarize the current knowledge on mechanisms of FLT3 activity regulation and its cellular consequences. Furthermore, we discuss how aberrant FLT3 signalling cooperates with other oncogenic lesions and the microenvironment to drive haematopoietic malignancies and how this can be harnessed for therapeutical purposes. Full article

(This article belongs to the Special Issue Protein Kinase in Leukemia)

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