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Biochemical discovery of new epigenetic pathways linked to leukemia

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Background: MLL1-rearrangements are thought to cause leukemia by inappropriately maintaining the expression of several transcription factors that promote self-renewal through epigenetic mechanisms. Both histone modifications, particularly the H3K79 methylation installed by the DOT1L enzyme, as well as 5-methyl cytosine adducts, such as 5-hydroxymethylC (5hmC) in DNA installed by the TET1/2 oxidases, are thought to play essential roles in both the initiation and progression of MLL-rearranged leukemias. The latter DNA modification enzymes are also implicated as both oncogenes and tumor suppressor in other leukemias, as well as skin and colon cancers. As there are no known specific binders for either of these epigenetic marks, the pathways by which they act remain completely obscure. Consequently, our understanding of the molecular mechanisms by which they allow MLL1-r-mediated cancer to develop and self-renew remains limited.

Objective/Hypothesis: We have identified several highly-specific binding factors specific for two “orphaned” epigenetic marks that are essential in the etiology of MLL1-r mediated cancers. We seek to understand how these proteins act locally to promote gene expression in cancer and normal contexts.

Specific Aims: (1) To characterize specific H3K79me-binding partners and investigate their functional roles in leukemia; (2) To characterize specific 5hmC-binding partners and investigate their functional roles leukemia.

Study design: The first aim focuses on novel pathways emanating from H3K79me2 that have resisted discovery for more than a decade. Pull-downs that leverage our unique semisynthetic nucleosomes coupled to quantitative proteomics have enabled discovery of specific binding partners for this mark. We plan to characterize the molecular principles that underlie the specificity and illuminate the pathway by which this mark seemingly promotes inappropriate transcriptional activation. The second aim is centered the hypothesis is that newly appreciated oxidative adducts of 5mC, rather acting as passive intermediates in a slow removal pathway, may function as epigenetic marks to recruit proteins distinct from those that bind the 5mC precursor. In support, we have identified specific binding partners for one of these bases and propose using these binding proteins as entry points to drive elucidation of the pathways by which these marks function.

Cancer relevance: These studies will reveal new epigenetic pathways that appear to be important for the etiology and maintenance of MLL-rearranged leukemias, providing a molecular understanding of these cancers. DOT1L is already targeted-therapeutically in leukemia although resistance mechanisms for these drugs appear to exist. Thus the downstream molecular players that we identify for H3K79me as well as 5hmC, like epigenetic “reader” proteins in other cancer contexts, will be high impact therapeutic targets.
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