Src Kinases in Ph+ Lymphoblastic Leukemia

描述（由申请方提供）：由BCR-ABL癌基因诱导的人费城染色体阳性（Ph+）白血病，包括慢性髓性白血病（CML）和B细胞急性淋巴细胞白血病（B-ALL），是最常见的血液恶性肿瘤。 BCR-ABL酪氨酸激酶抑制剂STI 571（Gleevec）在治疗慢性期CML患者中非常有效，但在治疗CML急变和Ph+ B-ALL患者中效果差得多。 此外，新出现的对STI 571的临床耐药性要求开发新的治疗策略。 确定BCR-ABL诱导B-ALL的关键信号通路对于理解疾病的病理生理学和开发有效的治疗方法至关重要。 我们已经建立了有效和准确的人Ph+白血病小鼠模型，以测试我们的总体假设，即BCR-ABL诱导淋巴和髓系白血病，但不同的信号转导途径在这两个细胞系中使用。 为了支持这一假设，我们鉴定了三种Src家族激酶（林恩、Hck和Fgr）作为BCR-ABL诱导的B-ALL而不是CML发展中的关键信号分子（Nature Genetics 36，453 -461，2004）。 因此，我们假设BCR-ABL表达淋巴样细胞中Src激酶信号通路与髓样细胞中的不同。 我们还发现，STI 571抑制BCR-ABL激酶不会减少BCR-ABL刺激的Src激活，而使用Src激酶抑制剂会减少对ST 1571耐药的BCR-ABL表达细胞的增殖并诱导其凋亡。 这些结果表明，Src激酶的激活是独立的BCR-ABL激酶活性。 因此，我们进一步假设Ph+ B-ALL的治疗需要同时抑制BCR-ABL激酶（STI 571）和Src激酶（Src激酶抑制剂）的功能。 为了验证这些假设，我们将采取生物化学和遗传学的方法来研究Src激酶被BCR-ABL激活的分子机制，并参与B淋巴细胞和B-ALL发展中的BCR-ABL信号传导。 我们还将使用我们的小鼠模型进一步评估Src激酶作为B-ALL治疗靶点的用途。

DESCRIPTION (provided by applicant): Human Philadelphia chromosome-positive (Ph+) leukemias induced by the BCR-ABL oncogene, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL), are among the most common hematologic malignancies. The BCR-ABL tyrosine kinase inhibitor STI571 (Gleevec) is highly effective in treating chronic phase CML patients, but is much less effective in treating CML blast crisis and Ph+ B-ALL patients. Moreover, the emerging clinical resistance to STI571 begs for development of new therapeutic strategies. Determination of the key signaling pathways utilized by BCR-ABL to induce B-ALL is crucial for understanding the pathophysiology of the disease and for developing effective therapies. We have established efficient and accurate mouse models of human Ph+ leukemias to test our overall hypothesis that BCR-ABL induces both lymphoid and myeloid leukemias, but different signaling pathways are utilized in these two cell lineages. In support of this hypothesis, we identified three Src family kinases (Lyn, Hck, and Fgr) as key signaling molecules in the development of BCR-ABL-induced B-ALL but not CML (Nature Genetics 36,453-461, 2004). Therefore, we hypothesize that Src kinase signaling pathways in BCR-ABL-expressing lymphoid cells are different from those in myeloid cells. We have also found that inhibition of BCR-ABL kinase by STI571 does not reduce BCR-ABL-stimulated Src activation, whereas use of a Src kinase inhibitor reduces proliferation and induces apoptosis of BCR-ABL-expressing cells that are resistant to ST1571. These results suggest that the activation of Src kinases is independent of BCR-ABL kinase activity. Therefore, we further hypothesize that simultaneous inhibition of functions of both BCR-ABL kinase (by STI571) and Src kinases (by a Src kinase inhibitor) is needed for therapy of Ph+ B-ALL. To test these hypotheses, we will take biochemical and genetic approaches to study the molecular mechanism by which Src kinases are activated by BCR-ABL and are involved in BCR-ABL signaling in B-lymphoid cells and B-ALL development. We will also further evaluate the use of Src kinases as therapeutic targets for B-ALL using our mouse model.