High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Longlong Liu; Pradeep Kumar Patnana; Xiaoqing Xie; Daria Frank; Subbaiah Chary Nimmagadda; Annegret Rosemann; Marie Liebmann; Luisa Klotz; Bertram Opalka; Cyrus Khandanpour

doi:10.3390/cancers14030486

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

Cancers (Basel). 2022 Jan 19;14(3):486. doi: 10.3390/cancers14030486.

Authors

Affiliations

¹ Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany.
² Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
³ Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, 48149 Muenster, Germany.
⁴ Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, 48149 Muenster, Germany.
⁵ Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, University of Lübeck, 23562 Lübeck, Germany.

Abstract

Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin.

Keywords: MLL/AF9; OXPHOS; heterogeneity; metformin.