Abstract 44: Leukemia-associated DNMT3A R882 mutations and their role in anthracycline-induced DNA damage response and therapeutic resistance

Despite significant advances in cancer research and treatment, therapeutic resistance remains a major obstacle for achieving stable remission in cancer patients. Acute myeloid leukemia (AML) is no exception, and most AML patients develop resistance to chemotherapy/targeted therapies, which results in disease relapse and progression. Recurrent mutations in the DNA methyltransferase 3A (DNMT3A) gene have been identified in 20-30% of AML cases and are predictive of unfavorable prognosis in patients treated with standard anti-leukemic regimens. In addition, DNMT3A-mutant AMLs appear to be relatively refractory to anthracycline family chemotherapeutics, such as daunorubicin. Half of all DNMT3A mutations affect amino acid residue R882, and recent work has shown that these mutants display decreased enzymatic activity and aberrant binding properties. In addition, previous studies have shown that wild-type DNMT3A functions as a pro-apoptotic switch in response to genotoxic stress induced by another anthracycline doxorubicin. We propose that mutant DNMT3A protects cells from apoptosis in response to DNA damage by altering molecular machinery involved in DNA-damage sensing, response and/or repair, through DNA methylation-dependent or independent mechanisms. Specifically, our data show that mutant DNMT3A affects recruitment of DNA repair proteins to chromatin, including aberrant distribution of homologous recombination marker RAD51. We are currently investigating molecular changes in DNA damage response in DNMT3A-mutant cells in vitro and ex vivo, and leukemogenic potential of the mutant Dnmt3a allele in vivo, whether alone or in combination with other cooperating oncogenes. Citation Format: Olga A. Guryanova, Kaitlyn Shank, Luisa Luciani, Evangelia Loizou, Matthew D. Keller, Abby R. Weinstein, Omar Abdel-Wahab, Siddhartha Mukherjee, Stephen S. Nimer, Ross L. Levine. Leukemia-associated DNMT3A R882 mutations and their role in anthracycline-induced DNA damage response and therapeutic resistance. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 44. doi:10.1158/1538-7445.CANSUSC14-44