源自T-原淋巴细胞白血病的SEPT9-ABL1嵌合融合基因的功能分析
Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia.
作者信息
Kawai Hidetsugu, Matsushita Hiromichi, Suzuki Rikio, Sheng Yin, Lu Jun, Matsuzawa Hideyuki, Yahata Takashi, Tsuma-Kaneko Mitsuyo, Tsukamoto Hideo, Kawada Hiroshi, Ogawa Yoshiaki, Ando Kiyoshi
机构信息
Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan.
出版信息
Leuk Res. 2014 Dec;38(12):1451-9. doi: 10.1016/j.leukres.2014.08.015. Epub 2014 Aug 30.
We analyzed the function of a SEPT9-ABL1 fusion identified in a case of T-prolymphocytic leukemia with tyrosine kinase inhibitor (TKI) resistance. Five isoforms with different N-termini, including SEPT9a-ABL1, SEPT9b-ABL1, SEPT9d-ABL1, SEPT9e-ABL1 and SEPT9f-ABL1, were detected in the leukemic cells. All isoforms except SEPT9d-ABL1 are localized in the cytoplasm, undergo autophosphorylation and phosphorylate the downstream targets, STAT-5 and Crkl, and provided IL-3-independence and in vivo invasiveness to 32D cells. Additionally, these SEPT9-ABL1 isoforms were resistant to TKIs in vitro and in vivo, in comparison to BCR-ABL1. These findings demonstrated that SEPT9-ABL1 had oncogenic activity and conferred resistance to TKIs.
我们分析了在一例对酪氨酸激酶抑制剂（TKI）耐药的T-原淋巴细胞白血病病例中鉴定出的SEPT9-ABL1融合蛋白的功能。在白血病细胞中检测到了5种具有不同N端的异构体，包括SEPT9a-ABL1、SEPT9b-ABL1、SEPT9d-ABL1、SEPT9e-ABL1和SEPT9f-ABL1。除SEPT9d-ABL1外，所有异构体均定位于细胞质中，进行自磷酸化并磷酸化下游靶点STAT-5和Crkl，并赋予32D细胞IL-3非依赖性和体内侵袭性。此外，与BCR-ABL1相比，这些SEPT9-ABL1异构体在体外和体内均对TKI耐药。这些发现表明，SEPT9-ABL1具有致癌活性并赋予对TKI的耐药性。
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