Mechanism of Ikaros Tumor Suppression in progenitor B cell leukemia

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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.