Studies of BCR-ABL leukemogenesis in mice

描述（由申请人提供）： 费城染色体阳性（Ph+）白血病，包括慢性粒细胞白血病（CML）和Ph+ B细胞急性淋巴细胞白血病（B-ALL），是一种常见的血液肿瘤，目前的治疗方法尚不足以治疗。虽然BCR-ABL 1酪氨酸激酶抑制剂（TKI）如甲磺酸伊马替尼已取代造血干细胞移植（HSCT）作为CML的初始治疗，但完全的分子缓解很罕见，对TKI治疗的获得性耐药是一个重要的临床问题。符合条件的Ph+ B-ALL患者在化疗后首次缓解时接受同种异体HSCT，但超过一半会复发。因此，目前的治疗可能无法治愈大多数Ph+白血病患者，需要有效的方法来根除残留的白血病。为了实现这些目标，将利用充分表征的CML和B-ALL小鼠模型来确定这些疾病的发病机制，以鉴定对白血病发生和白血病起始或白血病干细胞发生至关重要的信号通路，并最终验证这些通路作为治疗靶点，并进行分子靶向药物的临床前测试。总之，这些研究应该产生重要的新知识，将提高我们目前治疗Ph+白血病的有效性，并增加治愈患者的比例。

DESCRIPTION (provided by applicant): Project Summary The Philadelphia chromosome-positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. To accomplish these goals, well-characterized mouse models of CML and B-ALL will be utilized to determine the mechanisms of pathogenesis of these diseases, to identify signaling pathways critical to leukemogenesis and to the genesis of leukemia-initiating or leukemia stem cels, and finally to validate these pathways as targets for therapy and conduct preclinical testing of molecularly targeted drugs. Together, these studies should yield important new knowledge that will improve the effectiveness of our current treatments for Ph+ leukemia, and increase the proportion of patients that are cured of their disease.