Cdk5 signaling in ICN1-induced T Cell Leukemogenesis

描述（由申请人提供）：白血病是儿童期最常见的恶性肿瘤。尽管联合化疗方案改善了结局，但白血病的治疗仍存在重大挑战，特别是在复发或中枢神经系统（CNS）阳性疾病患者中。骨髓和中枢神经系统在积极化疗期间充当白血病细胞的避难所，然后可以复发并扩散到其他器官。特别地，T细胞ALL（T-ALL），急性淋巴细胞白血病（ALL）的一种亚型，是具有浸润CNS倾向的侵袭性白血病。对于这些患者，需要探索治疗选择的新方向。大约60%的人T-ALL携带组成型活性蛋白，Notch 1的胞内结构域（ICN 1）。最近，我们与Lan Zhou博士合作，建立了一种疾病模型，其中携带ICN 1突变的T-ALL可以在活小鼠中从白血病前期到完全爆发的白血病进行跟踪。在与Letterio博士的合作中，Huang实验室发现了另一种信号蛋白Cdk 5，它在白血病细胞和活化淋巴细胞的生物学中非常重要。Cdk 5对ICN 1诱导的T-ALL发展的贡献，以及Cdk 5作为ALL治疗靶点的作用均未得到探索。在这里，我们组建了一个科学家团队来研究Cdk 5如何影响骨髓和CNS浸润期间ICN 1诱导的T-ALL肿瘤发生。我们将研究T-ALL的发展和他们的中枢神经系统播种能力，通过调节Cdk 5活性在白血病前淋巴母细胞使用谱系特异性Cdk 5基因敲除策略。细胞和分子生物学，免疫学和我们独特的活体双光子显微镜能力的应用相结合-这使得动态检测个体白血病前和白血病细胞的行为在骨髓和中枢神经系统的活小鼠-将被用来解决这些重要的问题。再加上目前正在I期临床试验中针对Cdk 5进行测试的药物，我们的研究为开发针对T-ALL和CNS白血病的新型生物制剂或免疫介导疗法提供了新的方向。

DESCRIPTION (provided by applicant): Leukemia is the most common malignancy in childhood. Despite improved outcomes with combination chemotherapy regimens, significant challenges remain in the treatment of leukemia, especially in patients suffering from relapse or central nervous system (CNS)-positive disease. The bone marrow and CNS serve as sanctuary sites for leukemic cells during active chemotherapy, which can then relapse and spread to other organs. In particular, T-cell ALL (T-ALL), a sub-type of acute lymphoblastic leukemia (ALL), is an aggressive leukemia with a propensity to infiltrate the CNS. For these patients, new directions in the treatment options need to be explored. Approximately 60% of human T-ALL harbors a constitutively active protein, the Intracellular Domain of Notch1 (ICN1). Recently, in collaboration with Dr. Lan Zhou, we have established a disease model in which T-ALL harboring ICN1 mutation can be followed from pre-leukemia to full-blown leukemia in live mice. In collaboration with Dr. Letterio, the Huang lab have identified another signaling protein, Cdk5, as being important in the biology of leukemic cells and activated lymphocytes. Neither the contribution of Cdk5 to ICN1-induced T-ALL development, nor the role of Cdk5 as a therapeutic target in ALL has been explored. Here, we have assembled a team of scientists to study how Cdk5 affects ICN1-induced T-ALL tumorigenesis in the marrow and during CNS infiltration. We will study T-ALL development and their CNS seeding capacity by modulating Cdk5 activity in pre-leukemic lymphoblasts using lineage-specific Cdk5 genetic knockout strategies. A combination of cellular and molecular biology, immunology and application of our unique intravital two-photon microscopy capability - which allows the detection of dynamic individual pre- leukemic and leukemic cell behavior in the bone marrow and CNS of live mice - will be used to address these important questions. Coupled with drugs currently being tested against Cdk5 in Phase-I clinical trials, our investigations offer a new direction in the development of novel biological agents or immune-mediated therapies against T-ALL and CNS leukemia.