Voisset Edwige, Brenet Fabienne, Lopez Sophie, de Sepulveda Paulo
INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105, Institute Paoli-Calmettes, CRCM-Cancer Research Center of Marseille, U1068 Marseille, France.
Cancers (Basel). 2020 Jul 21;12(7):1996. doi: 10.3390/cancers12071996.
Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80-90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins.
自作为病毒癌基因产物被发现以来，蛋白酪氨酸激酶已被公认为细胞转化和癌症进展的重要参与者。SRC家族激酶（SFKs）在正常造血过程中发挥着关键作用。毫不奇怪，它们在急性髓系白血病（AML）和肥大细胞增多症等血液系统恶性肿瘤中被过度激活，并且对于膜受体下游信号传导至关重要。由于底物数量众多、成员之间功能冗余以及使用的工具缺乏选择性，SFKs的确切作用难以界定。然而，大量研究积累了证据支持SFKs是AML和肥大细胞增多症合理的治疗靶点。这两种疾病由血液学领域熟知的两种相关受体酪氨酸激酶调节：FLT3和KIT。FLT3是AML中最常发生突变的基因之一，而KIT致癌突变发生在80 - 90%的肥大细胞增多症中。对致癌性FLT3和KIT信号传导的研究揭示了SFK家族成员的特定作用。本综述强调了SFKs在AML和肥大细胞增多症中的核心作用，以及它们与FLT3和KIT癌蛋白的相互联系。
