Three lines of evidence have converged to confirm the importance of epigenetic deregulation in leukemias: (i) The epigenome is markedly abnormal in leukemic cells;(ii) mutations in epigenetic regulators are very frequent in myeloid leukemias and (iii) drugs that modulate the epigenome (DNA methylation inhibitors, histone deacetylase inhibitors) are clinically effective in subsets of patients with myeloid leukemia. In the previous funding period, we developed a cellular screening system to identify drugs that reactivate the expression of an epigenetically silenced reporter gene. Using this model, we demonstrated that chromatin resetting and nucleosome depletion are key to reactivation of gene expression, and that demethylation is essential to ensure long term expression. We then screened a drug library of FDA approved compounds for single agent activity, as well as activity in combination with DNA methylation inhibitors. This screen identified dozens of drugs with epigenetic activity, including all three known epigenetic regulators in the library (decitabine, azacitidine, vorinostat). Some of the drugs identified have known anti-neoplastic properties (e.g. arsenic trioxide) but most did not, and instead were developed for other medical indications (e.g. cardiac drugs). Many of these drugs share the property of affecting calcium fluxes, and we traced their epigenetic effects to signaling through calmodulin kinase resulting in displacement of methyl-binding proteins. In the synergy screens, we found strong synergy between hypomethylators and DNA damaging agents such as carboplatin which we traced to disruption of binding by HP1, a chromatin regulator essential for gene silencing. Thus, we have identified new ways of reactivating gene expression that can be readily exploited therapeutically in clinical trials. These observations led to the hypotheses that drugs that work through therapeutic displacement of methyl-binding proteins and HP1 can augment epigenetic reprogramming of leukemic cells, and that these will increase the molecular and clinical efficacy of known epigenetic drugs. To test these hypotheses, we propose three specific aims: (1) Mechanism of action and therapeutic potential of drugs that reactivate gene expression through calcium signaling. (2) Mechanism of action and therapeutic potential of drugs that synergize with hypomethylating agents in activation of gene expression. (3) Clinical trials of novel, mechanism based DAC combinations in relapsed/refractory AML and MDS. This grant proposal aims at improving the efficacy of epigenetic therapy in myeloid leukemias, an approach that has already contributing to prolonging sun/ival in these diseases.

Public Health Relevance

This project aims at developing new strategies for epigenetic therapy - a form of anti-cancer therapy that relies on reprogramming the epigenome or reeducation of the cancer cells to become closer to normal cells. The strategy has been successful in the past, and the new treatments approaches developed have the potential to increase cure rates in myeloid leukemias and could also find wide application in oncology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Issa, Jean-Pierre; Garcia-Manero, Guillermo; Huang, Xuelin et al. (2015) Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 121:556-61
Huang, Xuelin; Ning, Jing; Wahed, Abdus S (2014) Optimization of individualized dynamic treatment regimes for recurrent diseases. Stat Med 33:2363-78
Yousefzadeh, Matthew J; Wyatt, David W; Takata, Kei-Ichi et al. (2014) Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet 10:e1004654
Grunwald, Michael R; Tseng, Li-Hui; Lin, Ming-Tseh et al. (2014) Improved FLT3 internal tandem duplication PCR assay predicts outcome after allogeneic transplant for acute myeloid leukemia. Biol Blood Marrow Transplant 20:1989-95
Su, Xiaoping; Malouf, Gabriel G; Chen, Yunxin et al. (2014) Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget 5:9864-76
Chae, Young Kwang; Dimou, Anastasios; Pierce, Sherry et al. (2014) The effect of calcium channel blockers on the outcome of acute myeloid leukemia. Leuk Lymphoma 55:2822-9
Konig, Heiko; Levis, Mark (2014) Is targeted therapy feasible in acute myelogenous leukemia? Curr Hematol Malig Rep 9:118-27
Galanis, Allison; Ma, Hayley; Rajkhowa, Trivikram et al. (2014) Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 123:94-100
Bottoni, Arianna; Calin, George A (2014) MicroRNAs as main players in the pathogenesis of chronic lymphocytic leukemia. Microrna 2:158-64
Zhang, Yun; Xiong, Shunbin; Li, Qin et al. (2014) Tissue-specific and age-dependent effects of global Mdm2 loss. J Pathol 233:380-91

Showing the most recent 10 out of 222 publications