Mechanism of Ikaros Tumor Suppression in progenitor B cell leukemia

项目总结/摘要： 在美国所有新诊断的癌症病例中，近10%是血液癌症。而且对于 在儿童和年轻人中，血癌是癌症死亡的主要原因。白血病是一种 发展中的祖血细胞，和最常见的亚型白血病在儿科患者是 前体B细胞急性淋巴细胞白血病（pre-B ALL）亚型。转录因子Ikaros是一种 是淋巴发育的关键调节因子，被认为是前B细胞中重要的肿瘤抑制因子 所有.在超过80%的BCR-ABL 1+（Ph+）前B ALL中，Ikaros缺失或突变， 与其他前B ALL亚型的预后不良相关。然而，在我们的研究中， 了解Ikaros如何在白血病中发挥重要的肿瘤抑制作用， 目前没有针对前B ALL中的Ikaros功能丧失的可用疗法。我们的总体假设是 非编码RNA的表达与白血病有关， 抑制子是调节白血病相关非编码RNA基因的表达。因此，我们的 设计实验来绘制前B ALL的非编码RNA，并确定直接调控蛋白。 Ikaros的基因靶点，以便更好地了解其肿瘤抑制功能。这些结果将 用于阐明白血病发生的机制，并将为测试新的 治疗高危B-ALL患儿。

PROJECT SUMMARY / ABSTRACT: Almost 10% of all newly diagnosed cancer cases in the US are cancers of the blood. Moreover, for children and young adults, blood cancer is the leading cause of cancer mortality. Leukemia is a cancer of developing progenitor blood cells, and the most common subtype of leukemia in pediatric patients is the precursor B-cell acute lymphoblastic leukemia (pre-B ALL) subtype. The transcription factor Ikaros is a critical regulator of lymphoid development and is recognized as an important tumor suppressor in pre-B ALL. Ikaros is deleted or mutated in over 80% of BCR-ABL1+ (Ph+) pre-B ALL and Ikaros mutations are associated with a poor prognosis in other subtypes of pre-B ALL. However, there is a critical gap in our understanding of how Ikaros exerts it important tumor suppressor role in leukemia, and there are currently no therapies available that target Ikaros loss-of-function in pre-B ALL. Our overall hypothesis is that non-coding RNA expression is linked to leukemia and that a major role of Ikaros as a tumor suppressor is to regulate leukemia-associated non-coding RNA gene expression. Accordingly, our experiments are designed to map the non-coding RNAs of pre-B ALL and to define the direct regulatory gene targets of Ikaros in order to better understand its tumor suppressor function. These results will be used to elucidate mechanisms of leukemogenesis and will provide an important model for testing new therapies for children affected by high-risk B-ALL.