Studies of BCR/ABL Leukemogenesis in Mice

描述（由申请人提供）：蛋白酪氨酸激酶（TKs）失调是大多数慢性骨髓增殖性疾病的病因，也与某些类型的急性淋巴细胞白血病/淋巴母细胞淋巴瘤（B细胞和T细胞来源）的发病机制有关。例子包括BCR-ABL融合TK，慢性髓性白血病（CML） Ph染色体易位的产物，以及最近发现的JAK2 V617F突变，在大多数真性红细胞增多症（PV）患者中发现。目前对这些疾病的治疗是足够的。正如甲磺酸伊马替尼（CML中BCR-ABL的小分子抑制剂）的成功所证明的那样，TK酶是这些恶性肿瘤药物开发的良好靶点。然而，CML的激酶抑制剂治疗受到疾病对抑制剂的获得性和原发性耐药的限制。此外，越来越多的人认识到单独使用激酶抑制剂不太可能治愈，因为引发和维持疾病的所谓白血病“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失调相关的血液系统恶性肿瘤的分子发病机制，以开发额外的靶向治疗，并制定克服或预防对激酶抑制剂的耐药性和根除疾病的策略。这些疾病的精确和定量小鼠模型是这项工作的重要工具，因为它们可以解决关于白血病发生机制的基本问题，这些问题很难或不可能通过研究原发性人类白血病细胞或细胞系来解决。这项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，来推进我们对这些疾病的分子病理生理学的理解。为实现这一目标，我们将实现两个相互依存、相互结合的具体目标。在第一个目标中，我们将分析这些疾病的分子发病机制，并确定对体内白血病发生至关重要的信号通路。这将通过多方面的方法来实现，包括TK突变体、信号分子靶向突变的小鼠品系以及靶向特定途径的小分子抑制剂。在第二个目的，白血病起始或白血病干细胞在这些不同的疾病将表型和功能特征。这些研究应该产生关于这些疾病的发病机制的重要新知识，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.