Mechanism(s) of TAL1- and NOTCH1-mediated Leukemogenesis

描述(申请人提供)：T细胞急性淋巴细胞白血病(T-ALL)是一种侵袭性的恶性肿瘤，占儿童ALL病例的15%，占成人ALL病例的25%。尽管T-ALL儿童的总体存活率有所提高，但25%的儿童复发，大多数儿童死于疾病。目前，T-ALL采用多药化疗，目前尚无靶向治疗方法。T-ALL主要是由TAL1和NOTCH1致癌通路激活引起的。我们已经证明Tal1通过干扰E蛋白而导致白血病，E蛋白是淋巴系统发育的关键调节因子。我们还发现Notch1的突变是一个重要的协同事件，并表明小鼠T-ALL的生长仍然依赖于Notch1。因此，TAL1和NOTCH1都有助于T-ALL的生长和存活，但目前尚不清楚是否只通过抑制NOTCH1就可以在体内限制人类T-ALL的生长，或者TAL1/E2A致癌途径是否也需要被靶向。该研究计划的总体目标是了解TAL1/E2A和NOTCH1通路是如何引起T-ALL的，并利用这一机制知识在我们的小鼠和新建立的人类T-ALL模型中测试新的治疗方法。我们假设，在T-ALL患者中观察到的高复发率反映了无法消除白血病起始细胞(L-IC)，这是一种罕见的白血病细胞群，需要启动和维持疾病。使用我们的小鼠T-ALL模型，我们证明了承诺的胸腺前体细胞具有丰富的疾病潜能，并且Notch1抑制降低了小鼠L-IC的活性。本研究的目的是对小鼠L-IC进行纯化和鉴定，并确定Notch1如何介导L-IC的自我更新，以及Tal1是否也起作用(Aim1)。我们的初步研究表明，沉默TAL1癌基因使人T-ALL细胞对NOTCH1抑制作用敏感，并诱导细胞凋亡。这项建议的最终目的是开发新的TAL1抑制剂，并测试TAL1和NOTCH1抑制是否足以消除人类L-IC并延长接种原代儿童T-ALL细胞的免疫缺陷NOD-SCID IL2R3缺失小鼠的生存时间。

DESCRIPTION (provided by applicant): T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for 15% of pediatric and 25% of adult ALL cases. Although the overall survival rates for children with T-ALL have improved, 25% relapse and most succumb to disease. Currently, T-ALL is treated with multi-agent chemotherapy and no targeted therapies exist. T-ALL is largely caused by activation of the TAL1 and NOTCH1 oncogenic pathways. We have shown that Tal1 contributes to leukemia by interfering with E proteins, critical regulators of lymphoid development. We also identified mutations in Notch1 as an important cooperating event and showed that mouse T-ALL growth remains dependent on Notch1. Therefore, both TAL1 and NOTCH1 contribute to T-ALL growth and survival, but it remains unknown whether human T-ALL growth can be limited in vivo by inhibiting only NOTCH1 or whether the TAL1/E2A oncogenic pathway will also need to be targeted. The overall goals of this research program are to understand how the TAL1/E2A and NOTCH1 pathways give rise to T-ALL and to use this mechanistic knowledge to test new therapeutic approaches in our mouse and newly established human T-ALL models. We hypothesize that the high rates of therapeutic relapse observed in T-ALL patients reflects an inability to eliminate leukemia-initiating cells (L-ICs), a rare population of leukemic cells required to initiate and perpetuate disease. Using our mouse T-ALL models, we demonstrate that committed thymic progenitors are enriched in disease potential and that Notch1 inhibition reduces mouse L-IC activity. A goal of this proposal is to purify and characterize the mouse L-IC and to determine how Notch1 mediates L-IC self-renewal and whether Tal1 also contributes (Aim1). Our preliminary studies show that silencing the TAL1 oncogene sensitizes human T-ALL cells to the effects of NOTCH1 inhibition and induces apoptosis. A final objective of this proposal is to develop novel TAL1 inhibitors and to test whether TAL1 and NOTCH1 inhibition is sufficient to eliminate human L-ICs and prolong the survival of immunodeficient NOD-scid IL2R3null mice engrafted with primary pediatric T-ALL cells.