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细胞前体细胞转化引起的疾病。它主要困扰儿童和青少年。尽管T-ALL的治疗结果近年来有所改善，但尽管使用了涉及造血干细胞移植的方案，复发患者的预后仍然很差。T-ALL患者在确诊时白细胞计数升高，肝脾肿大，中枢神经系统(CNS)复发的风险增加。出于这个原因，T-ALL患者通常在鞘内强化化疗的基础上接受颅脑照射。存活率的显著提高被认为值得与这种疗法相关的重大副作用。这些并发症包括继发性肿瘤、神经认知障碍、内分泌障碍和生长障碍。尽管白血病细胞侵袭中枢神经系统具有临床意义，但对其机制知之甚少。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黏附信号。CCR7基因的表达受T-ALL癌基因Notch1的活性控制，Notch1是这种疾病中最核心的癌基因，它在携带Notch1激活突变的人类肿瘤中表达。在T-ALL动物模型中，沉默CCR7或其趋化因子配体可特异性地抑制中枢神经系统的渗透。此外，人T-ALL细胞对CNS的靶向依赖于其表达CCR7的能力。所有这些观察使我们假设CCR7趋化因子受体及其配体是白血病细胞迁移/组织侵袭的有效调节因子，以响应致癌的Notch1信号。这一假设在本应用程序中得到了验证。靶向抑制T-ALL中CNS的参与可能会降低CNS靶向治疗的强度，从而减少治疗的短期和长期并发症。

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.