Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia Journal Article
| Authors: | Shih, A. H.; Meydan, C.; Shank, K.; Garrett-Bakelman, F. E.; Ward, P. S.; Intlekofer, A. M.; Nazir, A.; Stein, E. M.; Knapp, K.; Glass, J.; Travins, J.; Straley, K.; Gliser, C.; Mason, C. E.; Yen, K.; Thompson, C. B.; Melnick, A.; Levine, R. L. |
| Article Title: | Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia |
| Abstract: | Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2. Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stemprogenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML. © 2017 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 7 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-05-01 |
| Start Page: | 494 |
| End Page: | 505 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-16-1049 |
| PROVIDER: | scopus |
| PMCID: | PMC5413413 |
| PUBMED: | 28193779 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2017 -- Source: Scopus |
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