Frank Salituro

Abstract PL02-04: IDH mutations and tumorigenicity.

Mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes are present in ∼20% of acute myeloid leukemia, and cause a neomorphic enzyme activity that results in the production of 2-hydroxyglutarate (2HG). Mutational and epigenetic profiling of a large patient cohort of acute myeloid leukemia (AML) has revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and impaired hematopoietic differentiation. To further investigate the intrinsic effect of 2HG on hematopoietic proliferation and differentiation, we transfected an erythroleukemia cell line (TF-1) with either IDH1 or IDH2 mutant alleles. These cells overexpress the mutant enzyme, have high levels of 2HG, and exhibit GM-CSF independent growth. Consistent with clinical observations, overexpression of the IDH mutant proteins led to hypermethylation of both histones and DNA. These results suggest that mutations in IDH1/2 could lead to epigenetic rewiring of cells that could facilitate the gain of function phenotype. We are currently studying the global and specific effects of IDH1/2 mutant overexpression to gain a broader understanding of the biological consequence of the IDH1/2 gain of function mutations. We have also generated mutation selective molecules that are capable of inhibiting IDHm enzymes. Upon compound treatment in vitro, we are able to reverse hypermethylation of both histones and DNA and induce cellular differentiation in IDHm cell lines and primary human IDHm AML patient samples(1, 2). These data suggest that an inhibitor of IDH1/2 mutations could correct the altered gene expression patterns seen in IDH1/2 mutant AML tumors leading to a profound effect on hematopoietic differentiation, proliferation and tumor growth. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-04. Citation Format: F. Wang, J. Travins, B. DeLaBarre, V. Penard-Lacronique, S. Schalm, E. Hansen, K. Straley, A. Kernytsky, W. Liu, C. Gliser, H. Yang, S. Gross, E. Artin, V Saada, E. Mylonas, C. Quivoron, J. Popovici-Muller, J. O. Saunders, F. G. Salituro, S. Yan, S. Murray, W. Wei, Y. Gao, L. Dang, M. Dorsch, S. Agresta, D. P. Schenkein, S. A. Biller, S. M. Su, S. de Botton, Katharine E. Yen. IDH mutations and tumorigenicity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-04.

Abstract LB-164: IDH mutations and tumorgenicity

IDH mutations and tumorgenicity Kate Yen1, Fang Wang1, Sung Choe1, Stefanie Schalm1, Erica Hansen1, Kimberly Straley1, Janeta Popovici-Muller1, Jeremy Travins1, Hua Yang1, Lee Silverman1, William Kaelin2, Stefan Gross1, Lenny Dang1, Frank Salituro1, Jeff Saunders1, David Schenkein1, Michael Su1, Scott Biller1 Mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes are present in ∼16% of acute myeloid leukemia, and these mutations cause neomorphic enzyme activity that results in the production of 2-hydroxyglutarate (2HG). Mutational and epigenetic profiling of a large patient cohort of acute myeloid leukemia (AML) revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. To further investigate the intrinsic effect of 2HG on hematopoietic differentiation, we studied erythroleukemia cell lines transfected with IDH1 and IDH2 mutant alleles which overexpress the mutant enzyme, have high levels of 2HG, and exhibit GM-CSF independent growth. Further investigation showed that GATA1, a transcriptional factor known to direct myeloid differentiation, is also down-regulated by IDH2m in these cells along with its downstream direct target SLC4A1. These results demonstrate that the IDH2m can perturb the expression of transcription factors that could lead to alterations in myeloid differentiation. These data suggest that an inhibitor of IDH1/2 mutations could correct for the altered gene expression patterns seen in IDH1/2 mutant AML tumors leading to a profound effect on hematopoietic differentiation, proliferation and tumor growth. We are currently studying the global effects of IDH1/2 mutant overexpression on the methylation of histones and DNA to have a broader understanding of the biological consequence of the IDH1/2 gain of function mutations. Furthermore, treatment of these cell lines with compounds specific for either IDH1 or IDH2 mutant enzymes has a profound effect on their biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-164. doi:1538-7445.AM2012-LB-164