The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors
The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors
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DOI：
10.1038/leu.2012.240
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发表时间：
2013-02-01
期刊：
影响因子：
11.4
通讯作者：
Recher, C.
中科院分区：
文献类型：
--
作者：
Fialin, C.;Larrue, C.;Recher, C.
几种受体酪氨酸激酶（TKs）参与急性髓性白血病（AML）的发病机制。在这里，我们评估了白血病细胞系和AML患者样本中原始南泰受体（RON）的表达。在86例AML患者中，我们发现RON的全长和/或短形式（sf）分别在51%和43%的病例中表达。有趣的是，sfRON在正常的CD34+造血细胞中不表达，并通过与Src激酶Lyn相互作用诱导其部分致癌信号传导。在白血病细胞中，sfron介导的信号通路也涉及促凋亡bcl2家族成员mTORC1和BAD，但不涉及磷脂酰肌醇3-激酶/Akt通路。此外，5-氮杂胞苷（AZA）特异性下调sfRON的表达。相反，AZA可以在sfRON阴性的白血病细胞中诱导sfRON的表达，这表明该药物在AML和骨髓增生异常综合征中的活性可能与TKs的调节有关。cMET/RON抑制剂仅在AML样品和表达sfRON的细胞系中表现出抗白血病活性。这些结果可能支持在表达sfRON的AML患者中评估cMET/RON抑制剂的临床试验。白血病杂志，2013,27,325-335；doi: 10.1038 / leu.2012.240
Several receptor tyrosine kinases (TKs) are involved in the pathogenesis of acute myeloid leukemia (AML). Here, we have assessed the expression of the Recepteur d'Origine Nantais (RON) in leukemic cell lines and samples from AML patients. In a series of 86 AML patients, we show that both the full length and/or the short form (sf) of RON are expressed in 51% and 43% of cases, respectively. Interestingly, sfRON is not expressed in normal CD34+ hematopoietic cells and induces part of its oncogenic signaling through interaction with the Src kinase Lyn. sfRON-mediated signaling in leukemic cells also involves mTORC1, the proapoptotic bcl2-fannily member, BAD, but not the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, the expression of sfRON was specifically downregulated by 5-azacytidine (AZA). Conversely, AZA could induce the expression of sfRON in sfRON-negative leukemic cells suggesting that the activity of this drug in AML and nnyelodysplastic syndromes could involve modulation of TKs. cMET/RON inhibitors exhibited an antileukemic activity exclusively in AML samples and cell lines expressing sfRON. These results might support clinical trials evaluating cMET/RON inhibitors in AML patients expressing sfRON. Leukemia (2013) 27, 325-335; doi:10.1038/leu.2012.240