Abstract
Simple SummaryAcute myeloid leukemia (AML) is a haematologic disease in which oncogenic mutations in the receptor tyrosine kinase FLT3 frequently lead to leukaemic development. Potent treatment of AML patients is still hampered by inefficient targeting of leukemic stem cells expressing constitutive active FLT3 mutants. This review summarizes the current knowledge about the regulation of FLT3 activity at cellular level and discusses therapeutical options to affect the tumor cells and the microenvironment to impair the haematological aberrations. 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.
Highlights
Fms-like tyrosine kinase 3 (FLT3) is a member of the PDGFR receptor-tyrosine kinase (RTK) family and is expressed in human CD34+ haematopoietic stem cells (HSC), lymphoid progenitors, and progenitors cells of the granulocyte/macrophage lineage, including the common myeloid progenitor and the granulocyte/macrophage progenitors
To decipher the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles at diagnosis in patients at the chronic phase and in blast crisis showed that increased abundance of FLT3-expressing cells attenuated imatinib-induced apoptosis [76]
The earliest indication resulted from mice co-expressing FLT3 internal tandem duplication (ITD) with either partial tandem duplication of the gene encoding the histone methyltransferase mixed-lineage leukaemia (MLL) [81] or a MLL-AF9 fusion protein [82]
Summary
Fms-like tyrosine kinase 3 (FLT3) is a member of the PDGFR (class III) receptor-tyrosine kinase (RTK) family and is expressed in human CD34+ haematopoietic stem cells (HSC), lymphoid progenitors, and progenitors cells of the granulocyte/macrophage lineage, including the common myeloid progenitor and the granulocyte/macrophage progenitors. FLT3 participates in the maintenance of pluripotent. HSC and contributes to proliferation and differentiation of B-cell progenitors, myelomonocytic and dendritic cells [1,2,3]
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