Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that 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 patients with acute myeloid leukaemia (AML). In particular, patients expressing FLT3 ITD (internal tandem duplications of the juxtamembrane domain of FLT3) correlate with poor patient survival. Targeting FLT3-mutated leukaemic stem cells is therefore a key to the efficient treatment of patients with relapsed/refractory AML. The efficacy of approved tyrosine kinase inhibitors is regularly compromised by various resistance pathways or secondary mutations. Based on the current molecular understanding of aberrant signal transduction pathways and cell transformation, novel alternative treatment approaches can be exploited for therapeutic purposes. In particular, new insights into the regulation of the activity of counteracting protein tyrosine phosphatases (PTPs), the aberrant biogenesis and activation of mutant FLT3 proteins, as well as common factors controlling cell transformation are attractive avenues. This review summarises the current knowledge about the regulation of the oncogenic activities of mutant FLT3 proteins and discusses possible options for alternative treatments.
Fms样酪氨酸激酶3（FLT3）是一种受体酪氨酸激酶（RTK），参与淋巴系和髓系造血祖细胞的存活、增殖与分化。FLT3基因的致癌突变可导致组成型激活的FLT3变异体，常见于急性髓系白血病（AML）患者。特别是携带FLT3 ITD（FLT3近膜结构域内部串联重复）突变的患者，其生存预后普遍较差。因此，靶向FLT3突变的白血病干细胞是治疗复发/难治性AML患者的关键。已获批的酪氨酸激酶抑制剂的疗效常因多种耐药途径或继发性突变而受限。基于当前对异常信号转导通路和细胞转化的分子机制理解，可开发新型替代治疗方案用于临床治疗。尤其值得关注的是：拮抗性蛋白酪氨酸磷酸酶（PTPs）活性调控的新发现、突变FLT3蛋白异常生物合成与激活机制，以及控制细胞转化的共性调控因子，这些均为极具潜力的研究方向。本综述总结了当前关于突变FLT3蛋白致癌活性调控机制的研究进展，并探讨了替代治疗方案的潜在策略。
Targeting Oncogenic Activity and Signalling of Mutant Receptor Tyrosine Kinase FLT3
肿瘤(癌症)患者之家