TitleCombination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in - and -Mutant Acute Myeloid Leukemia.
Publication TypeJournal Article
Year of Publication2017
AuthorsShih, Alan H., Meydan Cem, Shank Kaitlyn, Garrett-Bakelman Francine E., Ward Patrick S., Intlekofer Andrew M., Nazir Abbas, Stein Eytan M., Knapp Kristina, Glass Jacob, Travins Jeremy, Straley Kim, Gliser Camelia, Mason Christopher E., Yen Katharine, Thompson Craig B., Melnick Ari, and Levine Ross L.
JournalCancer Discov
Date Published2017 May
KeywordsAminopyridines, Animals, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Dioxygenases, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, fms-Like Tyrosine Kinase 3, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Mice, Mice, Mutant Strains, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins, Signal Transduction, Triazines

<p>Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including and Here, we show that models of AML resulting from or mutations combined with 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 stem-progenitor 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. AMLs with mutations in or are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. .</p>

Alternate JournalCancer Discov
PubMed ID28193779
PubMed Central IDPMC5413413
Grant ListU54 OD020355 / OD / NIH HHS / United States
R01 CA173636 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35 CA197594 / CA / NCI NIH HHS / United States
K08 CA181507 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States