Althoff, M. J.; Minhajuddin, M.; Stevens, B.; Gillen, A. E.; Gipson, S.; Patel, S. B.; Shelton, I. T.; Miller, R.; Vujovic, A.; Krug, A.; Young, T.; Showers, W. M.; Dzieciatkowska, M.; Stephenson, D.; Tyagi, A.; Ellegast, J. M.; Wright, T.; Stegmaier, K.; Opferman, J. T.; D'Alessandro, A.; Smith, C. A.; Jordan, C. T.

While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 (ACSL1), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1, thereby promoting ven/aza-resistance in AML.