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

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

^*Corresponding author for this work

22 Citations (Scopus)

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.

Original language	English
Article number	486
Journal	Cancers
Volume	14
Issue number	3
ISSN	2072-6694
DOIs	https://doi.org/10.3390/cancers14030486
Publication status	Published - 01.02.2022

Funding

Funding: C.K. is supported partially by the Jose Carreras Leukaemia Foundation (DJCLS 17R/2018), by the Deutsche Krebshilfe (70112392), Deutsche Forschungsgemeinschaft (KH331/2-3), and the intramural funding of the Faculty of Medicine at University Hospital of Muenster (Kha2/002/20).

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers14030486

Cite this

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

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.",

author = "Longlong Liu and Patnana, \{Pradeep Kumar\} and Xiaoqing Xie and Daria Frank and Nimmagadda, \{Subbaiah Chary\} and Annegret Rosemann and Marie Liebmann and Luisa Klotz and Bertram Opalka and Cyrus Khandanpour",

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T1 - High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

AU - Liu, Longlong

AU - Patnana, Pradeep Kumar

AU - Xie, Xiaoqing

AU - Frank, Daria

AU - Nimmagadda, Subbaiah Chary

AU - Rosemann, Annegret

AU - Liebmann, Marie

AU - Klotz, Luisa

AU - Opalka, Bertram

AU - Khandanpour, Cyrus

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85122878972

U2 - 10.3390/cancers14030486

DO - 10.3390/cancers14030486

M3 - Journal articles

AN - SCOPUS:85122878972

SN - 2072-6694

VL - 14

JO - Cancers

JF - Cancers

IS - 3

M1 - 486

ER -

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

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

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