ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1.
ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1.
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DOI：
10.1038/leu.2010.268
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发表时间：
2011-02
期刊：
影响因子：
11.4
通讯作者：
Colicelli, J.
中科院分区：
文献类型：
--
作者：
Thai, M.;Ting, P. Y.;McLaughlin, J.;Cheng, D.;Mueschen, M.;Witte, O. N.;Colicelli, J.
ABL 基因易位产生组成型活性酪氨酸激酶，导致慢性粒细胞白血病、急性淋巴细胞白血病和其他造血系统恶性肿瘤。然而，ABL SH3/SH2 自抑制结构域的一致保留表明这些致白血病酪氨酸激酶融合蛋白仍然受到调节。我们解决了这个悖论，证明 BCR-ABL1 激酶活性受 RIN1（一种 ABL SH3/SH2 结合蛋白）调节。 BCR-ABL1 活性因 RIN1 过表达而增加，因 RIN1 沉默而降低。此外，根据生长因子独立性判断，Rin1−/− 骨髓细胞未被 BCR-ABL1、ETV6-ABL1 或 BCR-ABL1T315I（一种患者来源的耐药突变体）转化。异位 RIN1 的拯救验证了转化过程中与 BCR-ABL1 协作的细胞自主机制。 RIN1 沉默可增加对 ABL 激酶抑制剂伊马替尼的敏感性，这与 RIN1 稳定激活的 BCR-ABL1 构象（药物亲和力降低）一致。依赖 RIN1 激活来释放全部催化和细胞转化潜力揭示了一个以前未知的漏洞，可用于治疗 ABL 易位驱动的白血病病例。研究结果表明，RIN1 靶向可能对伊马替尼耐药疾病有效，并且可能在一线治疗中补充 ABL 激酶抑制剂。
ABL gene translocations create constitutively active tyrosine kinases that are causative in chronic myeloid leukemia, acute lymphocytic leukemia and other hematopoietic malignancies. Consistent retention of ABL SH3/SH2 autoinhibitory domains, however, suggests that these leukemogenic tyrosine kinase fusion proteins remain subject to regulation. We resolve this paradox, demonstrating that BCR-ABL1 kinase activity is regulated by RIN1, an ABL SH3/SH2 binding protein. BCR-ABL1 activity was increased by RIN1 overexpression and decreased by RIN1 silencing. Moreover, Rin1−/− bone marrow cells were not transformed by BCR-ABL1, ETV6-ABL1 or BCR-ABL1T315I, a patient-derived drug-resistant mutant, as judged by growth factor independence. Rescue by ectopic RIN1 verified a cell autonomous mechanism of collaboration with BCR-ABL1 during transformation. Sensitivity to the ABL kinase inhibitor imatinib was increased by RIN1 silencing, consistent with RIN1 stabilization of an activated BCR-ABL1 conformation having reduced drug affinity. The dependence on activation by RIN1 to unleash full catalytic and cell transformation potential reveals a previously unknown vulnerability that could be exploited for treatment of leukemic cases driven by ABL translocations. The findings suggest that RIN1 targeting could be efficacious for imatinib-resistant disease and might complement ABL kinase inhibitors in first-line therapy.
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影响因子：
50.3
作者：
Klemm L;Duy C;Iacobucci I;Kuchen S;von Levetzow G;Feldhahn N;Henke N;Li Z;Hoffmann TK;Kim YM;Hofmann WK;Jumaa H;Groffen J;Heisterkamp N;Martinelli G;Lieber MR;Casellas R;Müschen M
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Müschen M
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Cao, Xiaoqing;Tanis, Keith Q.;Colicelli, John
通讯作者：
Colicelli, John
影响因子：
32.4
作者：
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通讯作者：
Colicelli, J