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.
The proposed research is relevant to public health because understanding the epigenetic changes and deregulation of miR-9 expression in MLL-associated leukemia is ultimately expected to reveal therapeutically targetable genes, as well as potentially predicting which patient will respond best to which therapy. Thus, the proposed research is relevant to the NIH's mission that is dedicated to developing fundamental knowledge that will reduce the burdens of cancer biology and its impact on human health.
|Price, Colles; Chen, Jianjun (2014) MicroRNAs in Cancer Biology and Therapy: Current Status and Perspectives. Genes Dis 1:53-63|
|Chen, Ping; Price, Colles; Li, Zejuan et al. (2013) miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia. Proc Natl Acad Sci U S A 110:11511-6|