AMP-Activated Protein Kinase Contributes to Apoptosis Induced by the Bcl-2 Inhibitor Venetoclax in Acute Myeloid Leukemia

Noémie Legrand; Amandine Pradier; Laury Poulain; Sarah Mouche; Rudy Birsen; Clément Larrue; Federico Simonetta; Jerome Tamburini

doi:10.3390/cancers13235966

AMP-Activated Protein Kinase Contributes to Apoptosis Induced by the Bcl-2 Inhibitor Venetoclax in Acute Myeloid Leukemia

Cancers (Basel). 2021 Nov 27;13(23):5966. doi: 10.3390/cancers13235966.

Authors

Noémie Legrand^{1

2}, Amandine Pradier^{1

2}, Laury Poulain^{1

2}, Sarah Mouche^{1

2}, Rudy Birsen^{1

2

3}, Clément Larrue^{1

2}, Federico Simonetta^{1

2}, Jerome Tamburini^{1

2

3}

Affiliations

¹ Translational Research Centre in Onco-Hematology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
² Geneva University Medical Center, 1205 Geneva, Switzerland.
³ Institut Cochin, Université de Paris, INSERM U1016, F-75014 Paris, France.

Abstract

The treatment of acute myeloid leukemia (AML) remains a challenge especially among the elderly. The Bcl-2 inhibitor venetoclax recently showed significant survival benefits in AML patients when combined to low-dose cytarabine or azacitidine. Bcl-2 inhibition initiate mitochondrial apoptosis, but also respiration and cellular ATP production in AML. AMP-Activated Protein Kinase (AMPK) is a central energy sensor activated by increased AMP:ATP ratio to restore the cellular energy balance. Unexpectedly, we observed that venetoclax inhibited AMPK activity through caspase-dependent degradation of AMPK subunits in AML cells. On the other hand, genetic models of AMPK invalidation and re-expression suggested that AMPK participated to the early stages of apoptotic response through a negative regulation of multi-domain anti-apoptotic effectors such as Mcl-1 or Bcl-xL. Together our results suggested a new link between AMPK and Bcl-2-dependent mitochondrial apoptosis that participated to the anti-leukemic activity of venetoclax in AML.

Keywords: AML; AMPK; venetoclax.