Abstract
Simple SummaryAcute myeloid leukemia is a group of metabolic heterogeneous cancers, of which the long-term overall survival is still poor, especially in elderly patients. Targeting metabolic reprogramming in leukemic cells is becoming a promising strategy. The aim of our research was to explore the relation of genetic mutations with the metabolic phenotype and potential therapeutics to target metabolic pathway dependence. We confirmed the metabolic heterogeneity in AML cell lines and found the high dependence on oxidative phosphorylation in MLL/AF9 AML cells. Metformin could significantly repress the proliferation of MLL/AF9 AML cells by inhibiting oxidative phosphorylation.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.
Highlights
This article is an open access articleAcute myeloid leukemia (AML) is one of the most common and lethal leukemias in adults, with around 120,000 new cases every year worldwide [1,2]
We found that the inhibition of Oxidative phosphorylation (OXPHOS) by metformin significantly inhibited the proliferation of MLL/AF9 positive AML cells
Considering substantial metabolic heterogeneity among AML patients [12], and to assess whether there was an association of the genetic mutations with metabolic pathway dependence, we analyzed the bioenergetic profile of various human AML cell lines
Summary
Acute myeloid leukemia (AML) is one of the most common and lethal leukemias in adults, with around 120,000 new cases every year worldwide [1,2]. The long-term efficacy and the tolerability of these new drugs are yet to be proven. Accurate diagnosis stratification and therapeutic approaches with high efficiency and less toxicity are required to achieve remission and even long-term cure [6]. In this direction, targeting metabolic reprogramming in leukemic cells is becoming a promising strategy
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