Novel Approaches to Target Mutant FLT3 Leukaemia

SIMPLE SUMMARY: Acute 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. 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.