Epigenetic Regulation of Non-Coding RNA in Leukemia
Mutations in the de novo DNA methyltransferase DNMT3A are found in 23% of AML making it the most frequently mutated epigenetic modifier in AML. DNMT3A mutations are associated with shorter disease-free and overall survival in AML. We previously developed a spontaneous model of Dnmt3a-mutant AML (Meyer et al Cancer Discov, 2016). Our new studies using this AML model in parallel with primary human AML reveal the disruption of non-coding RNA genes. Given that approximately 80% of the genome is transcribed but only 3% encodes proteins, and virtually nothing is known about the regulation and function of non-coding RNA AML, this project aims to understand the epigenetic regulation of non-coding RNA that contribute to leukemogenesis and to use these novel findings for the development of novel treatment approaches.
Stem Cell-Associated miRNA in Leukemia
Kids can develop a variety of different types of myeloid leukemia, some very early in life. Mutations in the transcription factor GATA1 are found in nearly all cases of Down Syndrome (Trisomy 21) associated leukemia and these patients respond well to low-dose chemotherapy, while another common series of chromosomal translocations involving the MLL gene give rise to a more aggressive and difficult to treat type of childhood myeloid leukemia. We are interested in exploring the functional pathways of several small non-coding RNA, called microRNA (miRNA), in pediatric patients with these different types of myeloid leukemia. We have developed complex genetic models to mimic this disease in mice and to better understand how the expression of certain miRNA play a role in pediatric myeloid leukemia and how the miRNA effect treatment response.