Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells
Courtney L Jones, Brett M Stevens, Daniel A Pollyea, Rachel Culp-Hill, Julie A Reisz, Travis Nemkov, Sarah Gehrke, Fabia Gamboni, Anna Krug, Amanda Winters, Shanshan Pei, Annika Gustafson, Haobin Ye, Anagha Inguva, Maria Amaya, Mohammad Minhajuddin, Diana Abbott, Michael W Becker, James DeGregori, Clayton A Smith, Angelo D'Alessandro, Craig T Jordan, Courtney L Jones, Brett M Stevens, Daniel A Pollyea, Rachel Culp-Hill, Julie A Reisz, Travis Nemkov, Sarah Gehrke, Fabia Gamboni, Anna Krug, Amanda Winters, Shanshan Pei, Annika Gustafson, Haobin Ye, Anagha Inguva, Maria Amaya, Mohammad Minhajuddin, Diana Abbott, Michael W Becker, James DeGregori, Clayton A Smith, Angelo D'Alessandro, Craig T Jordan
Abstract
We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.
Keywords: NAD+; NAMPT; acute myeloid leukemia; leukemia stem cells; metabolism; nicotinamide; oxidative phosphorylation; relapse; therapy resistance; venetoclax.
Conflict of interest statement
Declaration of Interests D.A.P. receives research funding from Abbvie and has served as a consultant for Abbvie. C.L.J. is currently employed at the Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Copyright © 2020 Elsevier Inc. All rights reserved.
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Source: PubMed