Mechanisms of T cell leukemia induction and maintenance

T细胞白血病诱导和维持的机制

• 批准号: 8761342
• 负责人: Iannis Aifantis
• 金额: $ 34.11万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-27 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761342
• 关键词: Acute; Acute T Cell Leukemia; Address; Adhesions; Adolescent; Adverse effects; Animal Model; Blood; CCL19 gene; Candidate Disease Gene; Cell Adhesion; Cell Count; Cells; Central Nervous System Leukemia; Child; Cranial Irradiation; Data; Diagnosis; Disease; Disease Progression; Disease model; Endocrine System Diseases; Endothelium; Experimental Leukemia; Future; Gene Expression; Gene Targeting; Genes; Growth; Health; Hematopoietic Stem Cell Transplantation; Hepatosplenomegaly; Histology; Homing; Human; Image; Immune; Impairment; Infiltration; Intrathecal Chemotherapy; Leukemic Cell; Leukemic Infiltration; Leukocytes; Ligands; Lymphocyte; Lymphoid; Maintenance; Mediating; Metastatic Neoplasm to the Central Nervous System; Molecular Profiling; Mutation; Neoplasm Metastasis; Neuraxis; Neurocognitive Deficit; Oncogenes; Oncogenic; Organ; Paralysed; Patients; Process; Property; Protocols documentation; Recurrent disease; Recycling; Regulation; Relapse; Risk; Role; Signal Transduction; Site; Sphingosine-1-Phosphate Receptor; T-Cell Leukemia; T-Cell Transformation; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Treatment outcome; cell motility; cell transformation; chemokine; chemokine receptor; clinically significant; design; improved; in vivo; interest; knock-down; migration; notch protein; novel; outcome forecast; progenitor; receptor; relating to nervous system; research study; response; small hairpin RNA; therapeutic target; tumor

DESCRIPTION (provided by applicant): T cell acute lymphoblastic leukemia (T-ALL) is a disease induced by the transformation of T cell progenitors. It mainly afflicts children and adolescents. Although treatment outcome in T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis despite the use of protocols involving hematopoietic stem cell transplantation. T-ALL patients present at diagnosis with elevated white cell counts, hepatosplenomegaly, and are at elevated risk for central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The dramatic increase in survival is thought to be worth the significant side effects associated with this therapy. Such complications include secondary tumors, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukemic cell infiltration of the CNS despite its clinical significance. Here, we show using T-ALL animal modeling and gene-expression profiling that the chemokine receptor CCR7 is the essential adhesion signal required for the targeting of leukemic T-cells into the CNS. CCR7 gene expression is controlled by the activity of the T- ALL oncogene Notch1, the most central oncogene in this disease, and is expressed in human tumors carrying Notch1 activating mutations. Silencing of either CCR7 or its chemokine ligands in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, CNS targeting by human T-ALL cells depends on their ability to express CCR7. All these observations made us hypothesize that the CCR7 chemokine receptor and its ligands are potent regulator of leukemic cell migration/tissue infiltration in response to oncogenic Notch1 signaling. This hypothesis is tested in this application. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS targeted therapy, thus reducing short- and long-term complications of therapy.

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-ALL）是一种由T细胞祖细胞转化诱导的疾病。它主要影响儿童和青少年。尽管近年来T-ALL的治疗结果有所改善，但尽管使用了涉及造血干细胞移植的方案，复发性疾病患者的预后仍然很差。T-ALL患者在诊断时表现为白色细胞计数升高、肝脾肿大，并且中枢神经系统（CNS）复发的风险升高。因此，T-ALL患者除了接受强化鞘内化疗外，通常还接受颅照射。生存率的显著提高被认为是值得与这种疗法相关的显著副作用。这些并发症包括继发性肿瘤、神经认知缺陷、内分泌紊乱和生长障碍。白血病细胞浸润中枢神经系统的机制知之甚少，尽管其临床意义。在这里，我们使用T-ALL动物模型和基因表达谱显示趋化因子受体CCR 7是白血病T细胞靶向进入CNS所需的基本粘附信号。CCR 7基因表达受T-ALL癌基因Notch 1的活性控制，Notch 1是该疾病中最中心的癌基因，并且在携带Notch 1激活突变的人类肿瘤中表达。T-ALL动物模型中CCR 7或其趋化因子配体的沉默特异性抑制CNS浸润。此外，人T-ALL细胞的CNS靶向作用取决于其表达CCR 7的能力。所有这些观察使我们假设CCR 7趋化因子受体及其配体是响应致癌Notch 1信号传导的白血病细胞迁移/组织浸润的有效调节剂。在本申请中对该假设进行了测试。靶向抑制CNS参与T-ALL可能会降低CNS靶向治疗的强度，从而减少治疗的短期和长期并发症。