Studies of BCR/ABL Leukemogenesis in Mice

描述(申请人提供)：异常蛋白酪氨酸激酶(TKS)是大多数慢性骨髓增生性IKE疾病的原因，也与某些类型的B细胞和T细胞起源的急性淋巴细胞白血病/淋巴母细胞淋巴瘤的发病有关。例如慢性粒细胞白血病(CML)Ph染色体易位的产物BCR-ABL融合TK，以及最近在大多数真性红细胞增多症(PV)患者中发现的JAK2 V617F突变。目前对这些疾病的治疗是不够的。TK酶是这些恶性肿瘤药物开发的良好靶点，甲磺酸伊马替尼的成功就是例证，伊马替尼是CML中BCR-ABL的小分子抑制剂。然而，慢性粒细胞白血病的激酶抑制剂治疗受到该病对该抑制剂的获得性和原发耐药性的限制。此外，人们越来越认识到，单独使用激酶抑制剂不太可能治愈疾病，因为引发和维持这种疾病的所谓白血病“干细胞”对这些药物相对不敏感。需要更好地了解CML、PV、Ph+B细胞急性淋巴细胞白血病(B-ALL)和其他与TKS调节失调相关的血液系统恶性肿瘤的分子发病机制，以开发更多的靶向治疗方法，并建立克服或预防对激酶抑制剂的耐药性的策略，从而根除这种疾病。这些疾病的准确和定量的小鼠模型是这项工作的重要工具，因为它们可以解决有关白血病发生机制的基本问题，这些问题很难或不可能通过对原代人类白血病细胞或细胞系的研究来解决。这一竞争性更新应用的总体目标是利用已建立的Ph+白血病小鼠模型，包括BCR-ABL诱导的CML和B-ALL，以及一种新的PV模型，以促进我们对这些疾病的分子病理生理的理解。为实现这一目标，我们将落实两个相互依存、相互融合的具体目标。在第一个目标中，我们将分析这些疾病的分子发病机制，并确定在体内白血病发生中至关重要的信号通路。这将通过使用TK突变体、在信号分子中具有靶向突变的小鼠品系以及针对特定途径的小分子抑制剂的多方面方法来实现。在第二个目标中，这些不同疾病中的白血病起始干细胞或白血病干细胞将表现出表型和功能特征。这些研究应该会对这些疾病的发病机制产生重要的新知识，这将直接影响治疗的改进。

DESCRIPTION (provided by applicant): Dysregulated protein-tyrosine kinases (TKs) are the cause of most cases of chronic myeloproliferative- ike diseases, and have also been implicated in the pathogenesis of some types of acute lymphoid leukemia/ ymphoblastic lymphoma of both B cell and T cell origin. Examples include the BCR-ABL fusion TK, product of the Ph chromosome translocation in chronic myeloid leukemia (CML), and the recently discovered JAK2 V617F mutant, found in most patients with polycythemia vera (PV). Current therapy for these diseases is nadequate. The TK enzymes are good targets for drug development in these malignancies, as illustrated by the success of imatinib mesylate, a small molecule inhibitor of BCR-ABL in CML. However, kinase inhibitor therapy of CML is limited by acquired and primary resistance of the disease to the inhibitor. In addition, there is an increasing appreciation that kinase inhibitors are unlikely to be curative when used alone, because the so-called leukemia "stem cells" that initiate and maintain the disease are relatively insensitive to these drugs. A better understanding of the molecular pathogenesis of CML, PV, Ph+ B-cell acute lymphoblastic leukemia (B-ALL), and other hematologic malignancies associated with dysregulated TKs is needed to develop additional targeted therapies, and to build strategies to overcome or prevent resistance to kinase inhibitors and eradicate the disease. Accurate and quantitative mouse models of these diseases are essential tools in this effort, because they can address fundamental questions about mechanisms of leukemogenesis that are difficult or impossible to approach through studies of primary human leukemia cells or cell lines. The overall goal of this competing renewal application is to utilize established mouse models of Ph+ leukemia, including BCR-ABL-induced CML and B-ALL, and a new model of PV, to advance our understanding of the molecular pathophysiology of these diseases. To accomplish this goal, we will carry out two interdependent and integrated specific aims. In the first aim, we will analyze the molecular pathogenesis of these diseases and identify the signaling pathways that are critical for leukemogenesis in vivo. This will be accomplished through a multifaceted approach using TK mutants, mouse strains with targeted mutations in signaling molecules, and small molecule inhibitors targeting specific pathways. In the second aim, the leukemia-initiating or leukemia stem cells in these distinct diseases will be phenotypically and functionally characterized. These studies should generate important new knowledge about the pathogenesis of these diseases that will impact directly on improvements in therapy.