Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming

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Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming

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dc.contributor.author Bhanot, Haymanti en_US
dc.contributor.author Weisberg, Ellen L. en_US
dc.contributor.author Reddy, Mamatha M. en_US
dc.contributor.author Nonami, Atsushi en_US
dc.contributor.author Neuberg, Donna en_US
dc.contributor.author Stone, Richard M. en_US
dc.contributor.author Podar, Klaus en_US
dc.contributor.author Salgia, Ravi en_US
dc.contributor.author Griffin, James D. en_US
dc.contributor.author Sattler, Martin en_US
dc.date.accessioned 2017-12-06T05:52:42Z
dc.date.issued 2017 en_US
dc.identifier.citation Bhanot, Haymanti, Ellen L. Weisberg, Mamatha M. Reddy, Atsushi Nonami, Donna Neuberg, Richard M. Stone, Klaus Podar, Ravi Salgia, James D. Griffin, and Martin Sattler. 2017. “Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming.” Oncotarget 8 (40): 67639-67650. doi:10.18632/oncotarget.18797. http://dx.doi.org/10.18632/oncotarget.18797. en
dc.identifier.issn en
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492279
dc.description.abstract Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD. en
dc.language.iso en_US en
dc.publisher Impact Journals LLC en
dc.relation.isversionof doi:10.18632/oncotarget.18797 en
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620199/pdf/ en
dash.license LAA en_US
dc.subject acute myeloid leukemia (AML) en
dc.subject 6-phosphogluconate dehydrogenase (6PGD) en
dc.subject cancer metabolism en
dc.subject FLT3 en
dc.subject drug resistance en
dc.title Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming en
dc.type Journal Article en_US
dc.description.version Version of Record en
dc.relation.journal Oncotarget en
dash.depositing.author Bhanot, Haymanti en_US
dc.date.available 2017-12-06T05:52:42Z

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