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

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

doi:10.3390/cancers13235966

Noémie Legrand, Amandine Pradier + Show 6 more

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https://doi.org/10.3390/cancers13235966

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Abstract

Simple SummaryThe Bcl2 inhibitor venetoclax is a breakthrough therapy in acute myeloid leukemia (AML). We show that venetoclax induces caspase-dependent degradation of AMPK, a central regulator of cellular energy metabolism, with implications in the anti-Leukemic activity of venetoclax in AML.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.

Highlights

Acute myeloid leukemia results from the proliferation of bone marrow immature myeloid progenitor cells
As ATP depletion generally favors AMPK activation by increasing the AMP:ATP ratio, we investigated AMPK activity in acute myeloid leukemia (AML) cells incubated with venetoclax during short-term periods
AMPK phosphorylation at Thr172 was moderately inhibited in MOLM-14, and more strongly in OCI-AML2 and HL-60 cells, respectively, correlating with a proportional decrease of AMPKα amount, while both phospho-AMPK and AMPKα remained unaffected in the THP-1 cell line (Figure 1C)

Summary

Introduction

Acute myeloid leukemia results from the proliferation of bone marrow immature myeloid progenitor cells. In AML, venetoclax demonstrated on-target activity in preclinical models, and a meaningful efficacy as monotherapy in refractory/relapsed AML patients, and combined with low-dose cytarabine or azacytidine in previously untreated AML patients [4,5,6,7,8]. Bcl-2 regulates mitochondrial oxidative metabolism, as venetoclax was shown to inhibit electron transport chain complex I and to decrease oxygen consumption in AML [10]. In AML leukemic stem cells (LSCs) characterized by a low ROS content and a high Bcl-2 expression, venetoclax inhibits oxidative phosphorylation, resulting in the selective eradication of this tumor-promoting cell population, which might contribute to the meaningful activity of venetoclax observed in AML clinical trials [11,12]

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