B淋巴细胞特异性BCR-ABL致癌通路的鉴定与机制研究

BCR-ABL, which is generated by the Philadelphia chromosome (Ph+), is one of the best-known fusion genes in hematological malignancies. The chimeric protein is found in all of human chronic myelogenous leukemia (CML) and also accounts for approximately 20% of adult B-cell acute lymphoblastic leukemia (B-ALL) as well as 5% of pediatric B-ALL. BCR-ABL tyrosine kinase inhibitor (TKI) therapy has dramatically improved the outcome of CML. However, the poor efficacy of TKI is found in treating Ph+ B-ALL. The mechanism by which Ph+ B-ALL is less responsive to TKI is not clear. In our preliminary study, by using the mouse bone marrow transduction/transplantation model, we found that BCR-ABL with the deletion of the carboxyl terminal region (CTR) can still induce CML but not B-ALL. This result suggests that BCR-ABL/CTR is involved in the activation of B lymphocyte-specific oncogenic pathways. In this proposal，we will dissect the roles and functions of individual domains of BCR-ABL/CTR in inducing B-ALL. We will also identify signaling pathways activated through BCR-ABL/CTR in B lymphocytes. The identification of the B lymphocyte-specific oncogenic pathways by BCR-ABL would help to develop novel target therapies against Ph+ B-ALL and shed new lights into the mechanisms of myeloid vs. lymphoid leukemogenesis.

BCR-ABL是t(9;22)费城染色体异位（Ph+）产生的融合基因，能引起慢性粒细胞白血病（CML）及20％的成人急性B淋巴细胞白血病（B-ALL）。靶向BCR-ABL的酪氨酸激酶抑制剂（TKI）在治疗CML上获得了巨大成功，但对Ph+ B-ALL收效甚微。Ph+ B-ALL难治的机制尚不清楚。我们前期研究发现，删除羧基末端区域（CTR）的BCR-ABL仍能诱导小鼠发生CML，但无法引起B-ALL。此结果提示BCR-ABL/CTR参与了B淋巴细胞特异致癌通路的激活。探究BCR-ABL/CTR的结构与功能对揭示Ph+ B-ALL新的发病机制和治疗靶点有重要意义，同时对揭示淋巴细胞和髓细胞特异性致癌通路及治疗策略有重要理论意义。我们将分析BCR-ABL/CTR区域中不同的结构域在B-ALL发生中的作用，寻找CTR参与调节的信号通路，阐明B淋巴细胞特异性BCR-ABL致癌通路及机制。

BCR-ABL这一相同的遗传学特征能引起两类白血病CML和B-ALL，但两者在发生发展、疗效和预后方面迥然相异。.前期研究中，我们发现C末端缺失的BCR-ABL仍能使小鼠发生CML，但丧失了诱导B-ALL的能力，显然C末端缺失并未影响BCR-ABL的TKI活性。这一结果强烈提示我们，C末端之于BCR-ABL(+)B-ALL至关重要。.本研究发现在CTR不同结构域中，删除F-actin binding domain更能减弱BCR-ABL对B细胞的转化，延缓B-ALL发生。F-actin binding domain突变或缺失对BCR-ABL诱导CML和B-ALL有不同的影响：对CML发病影响小，但能极大延缓B-ALL小鼠的病程。F-actin binding domain突变是通过BCR-ABL412位点酪氨酸磷酸化水平下降而影响BCR-ABL在B-ALL中的致病能力。BCR-ABLY412F对CML的发病有一定影响，但直接导致B-ALL不发病。.我们将继续研究CTR在BCR-ABL(+)B-ALL的作用，寻找BCR-ABL C末端参与调节的信号通路，进一步探索C末端重要结构域对BCR-ABL相关信号通路的调节机制，以期发现新的治疗靶点，指导相应疾病的临床治疗。