The Oncogenic Role of miR-9 in MLL-Associated Leukemias

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): Leukemia remains a prominent cause of cancer-related death both in the United States and worldwide. MLL- associated leukemias represent a small amount (roughly 10%) of total acute leukemias and patients with MLL- translocations have poor prognosis. There is a fundamental gap in the understanding how MLL-translocations change the epigenetic machinery and transcription of target genes. As current therapies have proven inefficient in treating MLL-leukemias more study and research is required. The long-term goal is to identify a targeted therapy specific to MLL-translocations that compliments the routinely used chemotherapeutics. The objective in this thesis proposal is to determine the effects of MLL-induced changes in epigenetic machinery - specifically microRNA regulation and associated target genes - on leukemia initiation and development. The study of microRNAs is an emerging and innovative field of research. As a single microRNA has hundreds of putative targets understanding how microRNAs are aberrantly regulated in cancer has significant implications for understanding cancer and therapy. Specifically, expression-based analysis showed that microRNA-9 (miR- 9) is increased only in MLL-associated AML. Furthermore, miR-9's proposed target gene TGFBI, a known tumor suppressor in solid malignancies, is not expressed in MLL-leukemias. AKT, known to be regulated by TGFBI in solid malignancies, is over expressed in MLL-leukemias. Thus, the central hypothesis is that MLL- associated leukemias up-regulate miR-9 thus driving leukemogenesis through inhibition of TGFBI and subsequent activation of Akt. The rationale for the proposed research is that understanding the epigenetic changes in MLL-associated leukemia can generate targeted therapies. Guided by strong preliminary data, I will test the hypothesis in two specific aims: 1) to test the hypothesis that MLL-dependent activation of miR-9 enhances tumorigenesis in vivo; and 2) to test the hypothesis that TGFBI acts as a tumor suppressor through inhibition of AKT and thus blocking activation of B-catenin. Under the first aim, I will use chromatin immunoprecipitation to confirm MLL-truncations directly binds to the miR-9 promoter. Next, I will confirm that miR-9 expression is both necessary and sufficient for MLL-induced leukemia development. Under the second aim, I will test if expression of TGFBI suppresses MLL-leukemias. I will also test that TGFBI suppresses AKT and subsequently suppresses B-catenin - thus rendering MLL-leukemias sensitive to AKT and B-catenin targeted inhibition. This approach is innovative because it will determine if epigenetic induced changes in MLL-associated leukemias renders these leukemias sensitize to targeted chemotherapies. The proposed research is significant, because it will advance and expand understanding of how MLL-induced leukemias and how the epigenetic machinery can drive tumorigenesis. Ultimately, such knowledge has the ability to transform the treatment of MLL-associated leukemias, increase the survival of MLL-associated leukemia patients and reduce the growing burden on the cancer health care system in the United States.