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

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性恶性肿瘤，占儿童ALL病例的15%和成人ALL病例的25%。尽管T-ALL患儿的总体生存率有所提高，但仍有25%的患者复发，大多数患者死于疾病。目前，T-ALL的治疗采用多药化疗，尚无靶向治疗方法。T-ALL主要是由TAL1和NOTCH1致癌途径的激活引起的。我们已经证明Tal1通过干扰淋巴细胞发育的关键调节因子E蛋白而导致白血病。我们还发现Notch1的突变是一个重要的合作事件，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可以通过仅抑制NOTCH1来限制体内人类T-ALL的生长，或者TAL1/E2A致癌途径是否也需要靶向。本研究项目的总体目标是了解TAL1/E2A和NOTCH1通路如何引起T-ALL，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患者中观察到的高治疗复发率反映了无法消除白血病起始细胞（L-ICs），这是一种罕见的白血病细胞群，需要启动和延续疾病。利用我们的小鼠T-ALL模型，我们证明胸腺祖细胞具有丰富的疾病潜能，Notch1抑制降低了小鼠L-IC活性。本研究的目标是纯化和表征小鼠L-IC，并确定Notch1如何介导L-IC自我更新以及Tal1是否也有贡献（Aim1）。我们的初步研究表明，沉默TAL1癌基因使人T-ALL细胞对NOTCH1抑制的作用敏感，并诱导细胞凋亡。本研究的最终目标是开发新的TAL1抑制剂，并测试TAL1和NOTCH1抑制是否足以消除人类l - ic，并延长移植了原发性儿童T-ALL细胞的免疫缺陷NOD-scid IL2R3null小鼠的存活时间。

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.