Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia.
Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.
Mol Biol Rep. 2024 Apr 16;51(1):521. doi: 10.1007/s11033-024-09452-2.
Acute myeloid leukaemia (AML) is a complex haematological malignancy characterised by diverse genetic alterations leading to abnormal proliferation of myeloid precursor cells. One of the most significant genetic alterations in AML involves mutations in the FLT3 gene, which plays a critical role in haematopoiesis and haematopoietic homeostasis. This review explores the current understanding of FLT3 gene mutations and isoforms and the importance of the FLT3 protein in AML. FLT3 mutations, including internal tandem duplications (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD), occur in 25-30% in AML and are associated with poor prognosis. FLT3-ITD mutations lead to constitutive activation of the FLT3 signalling pathway, promoting cell survival and proliferation. FLT3-TKD mutations affect the tyrosine kinase domain and affect AML prognosis in various ways. Furthermore, FLT3 isoforms, including shorter variants, contribute to the complexity of FLT3 biology. Additionally, nonpathological polymorphisms in FLT3 are being explored for their potential impact on AML prognosis and treatment response. This review also discusses the development of molecular treatments targeting FLT3, including first-generation and next-generation tyrosine kinase inhibitors, highlighting the challenges of resistance that often arise during therapy. The final chapter describes FLT3 protein domain rearrangements and their relevance to AML pathogenesis.
急性髓系白血病（AML）是一种复杂的血液恶性肿瘤，其特征是多种遗传改变导致髓系前体细胞异常增殖。AML 中最显著的遗传改变之一涉及 FLT3 基因的突变，该基因在造血和造血稳态中起着关键作用。本综述探讨了 FLT3 基因突变和异构体的最新认识，以及 FLT3 蛋白在 AML 中的重要性。FLT3 突变，包括内部串联重复（FLT3-ITD）和酪氨酸激酶结构域（FLT3-TKD）点突变，在 AML 中发生率为 25-30%，与预后不良相关。FLT3-ITD 突变导致 FLT3 信号通路的组成性激活，促进细胞存活和增殖。FLT3-TKD 突变影响酪氨酸激酶结构域，并以多种方式影响 AML 的预后。此外，FLT3 异构体，包括较短的变体，增加了 FLT3 生物学的复杂性。此外，正在探索 FLT3 中的非病理性多态性，以了解其对 AML 预后和治疗反应的潜在影响。本综述还讨论了针对 FLT3 的分子治疗方法的发展，包括第一代和第二代酪氨酸激酶抑制剂，强调了治疗过程中经常出现的耐药性挑战。最后一章描述了 FLT3 蛋白结构域重排及其与 AML 发病机制的相关性。
