[FLT3 Mutations in Acute Myeloid Leukemia].

Tsukimi Shoji, Yuto Kida, Kouhei Yamashita, Satoshi Ichiyama
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引用次数: 0

Abstract

FMS-like tyrosine kinase 3 (FLT3), a class III tyrosine kinase receptor, plays an important role in the pro- liferation, survival, and differentiation of hematopoietic stem/progenitor cells. Approximately 30% of pa- tients with cytogenetically normal acute myeloid leukemia (CN-AML) harbor FLT3 mutations. The most frequent FLT3 mutations are internal tandem duplications (ITDs) in the juxtamembrane domain. FLT3-ITD mutations cause ligand-independent dimerization of FLT3 and the constitutive activation of its downstream signaling pathways, such as PI3K/AKT, A4APK/ERK, and STAT5, leading to dysregulated cellular prolifera- tion. The relapse risk of CN-AML patients with FLT3-ITD is higher and the overall survival (OS) of such patients is shorter than those of patients with wild-type FLT3. Recently genome-wide studies with next-generation sequencing have suggested that mutational combinations of genes related to signal transduction, transcription, splicing, cancer suppressors, and epigenetics contribute to the pathogenesis of AML. These mutations including FLT3-ITD may be prognostic factors facilitating the risk stratification for CN-AML. The point mutations D835/I836 in the tyrosine kinase domain (TKD) are detected in 5-7% of AML patients. The clinical relevance of these FLT3-TKD mutations remains unclear. FLT3-TKD mutations are detected even in patients treated with FLT3 inhibitors as secondary mutations, suggesting that the mutations are as- sociated with the resistance. Therefore, the detection of these mutations might provide us with the opportunity to consider appropriate treatment for patients. The molecular abnormalities in AML patients give us insights into the pathology of AML and clinically significant information required for the diagnosis, prognosis, and treatment decisions. [Review].

[FLT3突变在急性髓性白血病中的应用]。
fms样酪氨酸激酶3 (FMS-like tyrosine kinase 3, FLT3)是一类酪氨酸激酶受体,在造血干细胞/祖细胞的增殖、存活和分化中起重要作用。大约30%的细胞遗传学正常的急性髓性白血病(CN-AML)患者携带FLT3突变。最常见的FLT3突变是近膜结构域的内部串联复制(ITDs)。FLT3- itd突变导致FLT3不依赖配体的二聚化及其下游信号通路(如PI3K/AKT、A4APK/ERK和STAT5)的组成性激活,导致细胞增殖失调。CN-AML合并FLT3- itd患者复发风险高于野生型FLT3患者,总生存期(OS)短于野生型FLT3患者。最近,利用下一代测序技术进行的全基因组研究表明,与信号转导、转录、剪接、抑癌基因和表观遗传学相关的基因突变组合与AML的发病机制有关。包括FLT3-ITD在内的这些突变可能是促进CN-AML风险分层的预后因素。在5-7%的AML患者中检测到酪氨酸激酶结构域(TKD)的点突变D835/I836。这些FLT3-TKD突变的临床相关性尚不清楚。甚至在接受FLT3抑制剂治疗的患者中也检测到FLT3- tkd突变作为继发性突变,这表明这些突变与耐药相关。因此,这些突变的检测可能为我们提供机会考虑对患者进行适当的治疗。AML患者的分子异常为我们了解AML的病理以及诊断、预后和治疗决策所需的临床重要信息提供了依据。(审查)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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