Src Kinases in Ph+ Lymphoblastic Leukemia

描述(申请人提供)：由bcr-abl癌基因引起的人类费城染色体阳性(Ph+)白血病，包括慢性髓系白血病(CML)和B细胞急性淋巴细胞白血病(B-ALL)，是最常见的血液系统恶性肿瘤之一。BCR-ABL酪氨酸激酶抑制剂STI571(格列卫)对慢性期CML患者非常有效，但对CML急变期和Ph+B-ALL患者效果较差。此外，临床上出现的对STI571的耐药性要求开发新的治疗策略。确定BCR-ABL用于诱导B-ALL的关键信号通路对于了解疾病的病理生理学和开发有效的治疗方法至关重要。我们已经建立了高效、准确的人类Ph+白血病小鼠模型，以验证我们的总体假设，即BCR-ABL同时诱导淋巴系和髓系白血病，但这两种细胞系使用不同的信号通路。为了支持这一假说，我们确定了三个Src家族激酶(Lyn、HCK和FGR)是BCR-ABL诱导的B-ALL而不是CML发生发展的关键信号分子(自然遗传学36,453-461,2004)。因此，我们假设在表达bcr-abl的淋巴样细胞中的Src激酶信号通路与在髓系细胞中的不同。我们还发现，STI571抑制BCR-ABL激酶并不减少BCR-ABL刺激的Src激活，而使用Src激酶抑制剂则减少对ST1571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激酶的激活不依赖于bcr-abl激酶的活性。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(通过STI571)和Src激酶(由Src激酶抑制剂)的功能。为了验证这些假说，我们将采用生化和遗传学的方法来研究BCR-ABL激活Src激酶的分子机制，并参与B淋巴样细胞和B-ALL的BCR-ABL信号转导。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治疗靶点的使用。

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.