Campbell Family Cancer Research Institute, Ontario Cancer Institute, Toronto, Ontario, Canada.
Leukemia. 2013 Aug;27(8):1666-76. doi: 10.1038/leu.2013.40. Epub 2013 Feb 12.
Philadelphia chromosome-positive leukemias, including chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (B-ALL), are driven by the oncogenic BCR-ABL fusion protein. Animal modeling experiments utilizing retroviral transduction and subsequent bone marrow transplantation have demonstrated that BCR-ABL generates both myeloid and lymphoid disease in mice receiving whole bone marrow transduced with BCR-ABL. Y177 of BCR-ABL is critical to the development of myeloid disease, and phosphorylation of Y177 has been shown to induce GRB2 binding to BCR-ABL, followed by activation of the Ras and phosphoinositide 3 kinase signaling pathways. We show that the GRB2-related adapter protein, GADS, also associates with BCR-ABL, specifically through Y177 and demonstrate that BCR-ABL-driven lymphoid disease requires Gads. BCR-ABL transduction of Gads(-/-) bone marrow results in short latency myeloid disease within 3-4 weeks of transplant, while wild-type mice succumb to both a longer latency lymphoid and myeloid diseases. We report that GADS mediates a unique BCR-ABL complex with SLP-76 in BCR-ABL-positive cell lines and B-ALL patient samples. These data suggest that GADS mediates lymphoid disease downstream of BCR-ABL through the recruitment of specific signaling intermediates.
费城染色体阳性白血病，包括慢性髓性白血病和 B 细胞急性淋巴细胞白血病（B-ALL），是由致癌的 BCR-ABL 融合蛋白驱动的。利用逆转录病毒转导和随后的骨髓移植进行的动物模型实验表明，BCR-ABL 在接受整个骨髓转导的小鼠中产生髓系和淋巴系疾病BCR-ABL。BCR-ABL 的 Y177 对于髓系疾病的发展至关重要，并且已经表明 Y177 的磷酸化诱导 GRB2 与 BCR-ABL 结合，随后激活 Ras 和磷酸肌醇 3 激酶信号通路。我们表明，GRB2 相关衔接蛋白 GADS 也与 BCR-ABL 结合，特别是通过 Y177，并证明 BCR-ABL 驱动的淋巴系疾病需要 Gads。BCR-ABL 转导 Gads(-/-) 骨髓导致移植后 3-4 周内潜伏期短的髓系疾病，而野生型小鼠则死于潜伏期较长的淋巴系和髓系疾病。我们报告 GADS 介导 BCR-ABL 与 SLP-76 在 BCR-ABL 阳性细胞系和 B-ALL 患者样本中的独特 BCR-ABL 复合物。这些数据表明，GADS 通过募集特定的信号转导中间物来介导 BCR-ABL 下游的淋巴系疾病。
