Cdk5 signaling in ICN1-induced T Cell Leukemogenesis

ICN1 诱导的 T 细胞白血病发生中的 Cdk5 信号传导

基本信息

批准号：
8802979
负责人：
Alex Yee-Chen Huang
金额：
$ 20.68万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-07 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8802979
关键词：
Activated Lymphocyte Acute Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Affect Area B-Lymphocytes Biological Products Biology Blood - brain barrier anatomy Bone Marrow C57BL/6 Mouse CCL19 gene CCL21 gene Cell Cycle Kinetics Cell Lineage Cell Nucleus Cell Survival Cells Central Nervous System Leukemia Cephalic Chemotaxis Chemotherapy-Oncologic Procedure Childhood Clinical Trials Cognitive deficits Collaborations Combination Drug Therapy Complex Coupled Cranial Irradiation DNA-Binding Proteins Data Detection Development Disease Disease model Family Functional disorder Gene Deletion Genes Genetic Genetic Transcription Germ Lines Growth Hematologic Neoplasms Histone Deacetylase Human Imaging technology Immune Immunology In Vitro Incidence Individual Infiltration Intrathecal Chemotherapy Investigation Knock-out Knockout Mice Leukemic Cell Life Ligands Light Lymphoblastic Leukemia Lymphocyte Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Marrow Mediating Microscopy Modeling Molecular Target Molecular and Cellular Biology Morbidity - disease rate Mus Mutation Neoplasm Metastasis Neuraxis Organ Outcome Pathway interactions Patients Penetration Pharmaceutical Preparations Phase Phase I Clinical Trials Pilot Projects Precursor T-Lymphoblast Process Proteins Proto-Oncogene Proteins c-akt Relapse Research Resistance Resolution Role Scientist Seizures Signal Transduction Signaling Protein Site Staging Stem cells T-Cell Activation T-Cell Leukemia T-Lymphocyte Techniques Testing Thymus Gland Tissues Transcriptional Activation Transplantation Treatment Failure animal imaging cell behavior cell motility chemotherapy cranium design high risk human FRAP1 protein improved inhibitor/antagonist innovation insight leukemia leukemia treatment leukemogenesis lymphoblast member mortality mouse model notch protein novel progenitor promoter public health relevance receptor retroviral transduction success therapeutic target tumor tumorigenesis two-photon

项目摘要

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.

描述（由申请人提供）：白血病是儿童时期最常见的恶性肿瘤。尽管联合化疗方案改善了预后，但白血病的治疗仍然存在重大挑战，特别是患有复发或中枢神经系统（CNS）阳性疾病的患者。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，然后白血病细胞可能会复发并扩散到其他器官。特别是，T 细胞急性淋巴细胞白血病 (T-ALL) 是急性淋巴细胞白血病 (ALL) 的一种亚型，是一种具有浸润中枢神经系统倾向的侵袭性白血病。对于这些患者，需要探索治疗方案的新方向。大约 60% 的人类 T-ALL 含有一种组成型活性蛋白，即 Notch1 细胞内结构域 (ICN1)。最近，我们与周兰博士合作，建立了一种疾病模型，可以在活体小鼠中跟踪携带ICN1突变的T-ALL从白血病前期到成熟白血病的过程。黄实验室与 Letterio 博士合作，发现了另一种信号蛋白 Cdk5，它在白血病细胞和活化淋巴细胞的生物学中发挥着重要作用。既未探讨 Cdk5 对 ICN1 诱导的 T-ALL 发展的贡献，也未探讨 Cdk5 作为 ALL 治疗靶点的作用。在这里，我们组建了一个科学家团队来研究 Cdk5 如何影响 ICN1 诱导的骨髓中和中枢神经系统浸润过程中的 T-ALL 肿瘤发生。我们将通过使用谱系特异性 Cdk5 基因敲除策略调节白血病前期淋巴母细胞中的 Cdk5 活性来研究 T-ALL 的发育及其 CNS 播种能力。细胞和分子生物学、免疫学以及我们独特的活体双光子显微镜功能的应用相结合——可以检测活体小鼠骨髓和中枢神经系统中的动态个体白血病前期和白血病细胞行为——将用于解决这些重要的问题。结合目前正在 I 期临床试验中针对 Cdk5 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方向。