DMA methylation and associated epigenetic changes lead to functional alterations in pathways that promote neoplastic development. Therapy targeting DMA methylation and histone deacetylation, another epigenetic modification, has shown activity in myeloid leukemias, and is now part of standard of care in patients with myelodysplastic syndrome (MDS). We have identified a DMA hypermethylation signature that characterizes young patients with acute myeloid leukemia (AML) who have a high cure rate following standard cytotoxic chemotherapy. This signature was independent of known prognostic factors and, if validated, would provide an important tool towards personalized therapy in AML. Separately and paradoxically, we have shown that progression in AML (diagnosis to relapse) and in MDS (MDS to AML) is also associated with the progressive acquisition of aberrant DNA methylation that, in this situation, predicts for a poor overall outcome. Finally, in proof-of-concept studies, we have shown that treatment with the DNA methylation inhibitor DAC results in tumor-suppressor gene demethylation and reactivation in AML and MDS, associated with a relatively high response rate that correlates with induction of gene expression of the P15 tumor-suppressor. Based on these observations, we hypothesize that DNA methylation profiling identifies a subset of young patients with AML who are curable with standard chemotherapy. We further hypothesize that DNA methylation, through separate genes, also contributes to clonal evolution in AML, leading to relapses with drug resistant phenotypes, and that DNA methylation inhibition in remission will delay or eliminate clonal evolution and disease relapse in some patients. Finally, we hypothesize that strategies aimed at enhancing pharmacologic epigenetic reactivation will translate into better therapies for myeloid malignancies. To test these hypotheses, we propose the following specific aims: (1) Retrospectively and prospectively validate and extend an epigenetic signature of curability in AML. (2) Conduct a randomized clinical trial of remission maintenance in AML using DAC. (3) Use a methylated and silenced GFP reporter gene selectable system to identify key pathways and pharmacologic combinations that lead to epigenetic reactivation in neoplastic cells. This project will provide new markers of prognosis in AML and new approaches to therapy that are based on incorporating epigenetic modulation into the standard of care of this disease. Lay abstract: DNA methylation is a tag attached to DNA that modifies gene function by preventing RNA formation. Decitabine, a drug that modifies DNA methylation is useful in leukemia. We propose to verify that DNA methylation can identify patients who are curable with chemotherapy. We also propose to use decitabine to prevent relapse in AML, and we will find drugs that boost the activity of decitabine and that can be introduced into clinical trials

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National Cancer Institute (NCI)
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University of Texas MD Anderson Cancer Center
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Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564
Johanning, Gary L; Malouf, Gabriel G; Zheng, Xiaofeng et al. (2017) Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype. Sci Rep 7:41960
Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol 18:694-704
Kanagal-Shamanna, Rashmi; Loghavi, Sanam; DiNardo, Courtney D et al. (2017) Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica 102:1661-1670
Mu, Yunxiang; Zelazowska, Monika A; McBride, Kevin M (2017) Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene. J Exp Med 214:3543-3552
Kelly, A D; Kroeger, H; Yamazaki, J et al. (2017) A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 31:2011-2019
Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406
Pratz, Keith W; Levis, Mark (2017) How I treat FLT3-mutated AML. Blood 129:565-571
Kerros, Celine; Tripathi, Satyendra C; Zha, Dongxing et al. (2017) Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells. J Biol Chem 292:10295-10305
Kayser, Sabine; Levis, Mark J (2017) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol :

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