Mechanisms of T cell leukemia induction and maintenance

描述（申请人提供）：T细胞急性淋巴细胞白血病（T- all）是一种由T细胞祖细胞转化引起的疾病。它主要折磨儿童和青少年。尽管近年来T-ALL的治疗结果有所改善，但尽管采用了包括造血干细胞移植在内的治疗方案，复发患者的预后仍然很差。T-ALL患者在诊断时出现白细胞计数升高，肝脾肿大，并且中枢神经系统（CNS）复发的风险升高。因此，除了强化鞘内化疗外，T-ALL患者通常接受颅脑照射。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。尽管白血病细胞浸润中枢神经系统具有临床意义，但其机制尚不清楚。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CCR7是靶向白血病t细胞进入中枢神经系统所需的基本粘附信号。CCR7基因的表达受T- ALL癌基因Notch1的活性控制，Notch1是该疾病最核心的癌基因，在携带Notch1激活突变的人类肿瘤中表达。在T-ALL动物模型中沉默CCR7或其趋化因子配体特异性抑制中枢神经系统浸润。此外，人类T-ALL细胞靶向中枢神经系统取决于它们表达CCR7的能力。所有这些观察结果使我们假设CCR7趋化因子受体及其配体是响应致癌Notch1信号的白血病细胞迁移/组织浸润的有效调节剂。这个假设在这个应用程序中得到了验证。靶向抑制中枢神经系统参与T-ALL可能潜在地降低中枢神经系统靶向治疗的强度，从而减少治疗的短期和长期并发症。

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.