Studies of BCR-ABL leukemogenesis in mice

描述(由申请人提供)： 项目概述费城染色体阳性(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)，是目前治疗方法不足的常见血癌。虽然甲磺酸伊马替尼等bcr-abl1酪氨酸激酶抑制剂(TKI)已经取代造血干细胞移植(HSCT)作为CML的初始治疗方法，但分子完全缓解是罕见的，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-所有患者在化疗后首次缓解时都接受了异基因造血干细胞移植，但超过一半的患者将复发。因此，目前的治疗方法很可能不能治愈大多数Ph+白血病患者，需要有效的方法来根除残留白血病。为了实现这些目标，将利用具有良好特性的CML和B-ALL小鼠模型来确定这些疾病的发病机制，识别对白血病发生和白血病启动或白血病干细胞的形成至关重要的信号通路，最后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。总而言之，这些研究应该会产生重要的新知识，这些知识将改善我们目前治疗Ph+白血病的有效性，并增加患者治愈的比例。 公共卫生相关性： 尽管出现了治疗血癌(白血病)的新的“靶向”药物，但许多患者将无法治疗并复发。这项提案的目标是确定 某些类型白血病的基因变化实际导致疾病的方式，使用的是准确代表人类疾病的实验室小鼠。确定白血病的致病方式将导致治疗并最终治愈白血病患者的新方法。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Despite the advent of new "targeted" drugs for the treatment of blood cancer (leukemia), many patients will fail therapy and relapse. The goals of this proposal are to identify the ways that genetic changes in some types of leukemia actually cause the disease, using laboratory mice that are accurate representatives of the human disease. Identification of the ways leukemia is caused will lead to new approaches to treatment and ultimately cure of patients with leukemia.