Elsevier

Mitochondrion

Volume 21, March 2015, Pages 41-48
Mitochondrion

Review
Mitochondrial dependency in progression of acute myeloid leukemia

https://doi.org/10.1016/j.mito.2015.01.006Get rights and content

Highlights

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    Acute Myeloid Leukemia (AML) initiation, progression and maintenance have a mitochondrial dependency.

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    AML disease progression is dependent on mitochondrial oxidative phosphorylation and other mitochondrial metabolic pathways.

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    There is an interconnection between mitochondria regulated metabolism, cellular stress response pathways and AML.

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    Pharmacologically targeting various mitochondrial pathways help eradicating AML cells.

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    Mitochondrial pathways can be targeted for differentiation therapy to treat AML.

Abstract

Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disorder which arises due to dysregulated differentiation, uncontrolled growth and inhibition of apoptosis leading to the accumulation of immature myeloid progenitor in the bone marrow. The heterogeneity of the disease at the molecular and cytogenetic level has led to the identification of several alteration of biological and clinical significance. One of the alterations which have gained attention in recent times is the altered energy and metabolic dependency of cancer originally proposed by Warburg. Mitochondria are important cell organelles regulating cellular energetic level, metabolism and apoptosis which in turn can affect cell proliferation and differentiation, the major manifestations of diseases like AML. In recent times the importance of mitochondrial generated ATP and mitochondrial localized metabolic pathways has been shown to play important role in the progression of AML. These studies have also demonstrated the clinical significance of mitochondrial targets for its effectiveness in combating relapsed or refractory AML. Here we review the importance of the mitochondrial dependency for the progression of AML and the emergence of the mitochondrial molecular targets which holds therapeutic importance.

Section snippets

Acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by malignant clonal proliferation of immature myeloid progenitor cells in the bone marrow and peripheral blood. Commonly, AML is considered to be the result of genetic aberrations leading to irreversible deregulation of functions of genes critical for proliferation, differentiation, apoptosis and gene transcription. Based on the WHO 2008 classification, acute myeloid leukemia are classified as: acute myeloid leukemia with recurrent genetic

Altered metabolism in cancer and the mitochondria

Increasing evidences suggests that deranged metabolism is an important mechanism of cancer pathogenesis. More than fifty years ago Warburg hypothesized that altered metabolism was specific to cancer cells, and that it arose from mitochondrial defects that inhibited their ability to effectively oxidize glucose carbon to CO2 (Warburg, 1956). Warburg's hypothesis has been observed in a wide variety of cancers and has been exploited clinically by using 18-F-deoxyglucose positron emission tomography

Mitochondrial oxidative phosphorylation system and AML

Somatic and germline mutations of mtDNA have been studied across various types of cancer. These studies attempt to correlate mtDNA mutations with the OXPHOS function and its role in neoplastic transformation (Chatterjee et al., 2006). Earlier studies have shown that the mtDNA amounts are amplified in comparison to nDNA in the blast cells of AML (Boultwood et al., 1996). Studies of mtDNA mutation in both pediatric AML (Sharawat et al., 2009) and in adult AML (Silkjaer et al., 2013) showed

Mitochondrially localized metabolic pathways and AML

Mitochondria play the central role in maintaining energy and metabolic homeostasis in the cell. The core pathways contributing to the formation of NADH, NADPH and FADH2 which are essential for energy metabolism and generation of precursors for the synthesis of lipids, proteins and nucleic acids are mostly localized in the mitochondria. One of the most important links between mitochondrially localized pathways and AML progression is the identification of isocitrate dehydrogenase mutation in AML

Mitochondria interconnects metabolism with apoptosis redox signaling and autophagy — impact on AML progression

The altered metabolism in AML cells leads to an increased dependency on metabolic nutrients: glucose, glutamine and fatty acids. Deprivation of these nutrients or inhibition of their utilization has been shown to generate a cellular stress in the AML cells as discussed in the previous chapters. In this chapter we briefly describe how three vital responses of cellular stress: apoptosis, autophagy and redox imbalance, are related with the mitochondria and their metabolic activities. Mitochondria

Mitochondrial dependency: an emerging pharmacological target to eradicate AML cells

In this last section we summarize how the mitochondrial dependency for AML progression has led to potential therapeutic targets. The treatment for AML includes a course of intensive induction chemotherapy, followed by an additional course of intensive consolidation therapy and then maintenance therapy (Robak and Wierzbowska, 2009). The main aim of the therapeutic approaches is to eradicate the AML cells both the leukemic stem cells and the blast cells either by induction of apoptosis or

Acknowledgment

The study was funded by the Integrative Biology on Omics Platform (IBOP) project of Saha Institute of Nuclear Physics, Department of Atomic Energy, Govt. of India.

References (109)

  • L.M. Kats et al.

    Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance

    Cell Stem Cell

    (2014)
  • D.S. Krause et al.

    Right on target: eradicating leukemic stem cells

    Trends Mol Med

    (2007)
  • E.D. Lagadinou et al.

    BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells

    Cell Stem Cell

    (2013)
  • L. Li et al.

    Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation

    Cell Signal

    (2013)
  • J.E. Lindsley et al.

    Nutrient sensing and metabolic decisions

    Comp Biochem Physiol B Biochem Mol Biol

    (2004)
  • F. Lo-Coco et al.

    Understanding the molecular pathogenesis of acute promyelocytic leukemia

    Best Pract Res Clin Haematol

    (2014)
  • E.F. Mason et al.

    Cell metabolism: an essential link between cell growth and apoptosis

    Biochim Biophys Acta

    (2011)
  • D. Nowak et al.

    Differentiation therapy of leukemia: 3 decades of development

    Blood

    (2009)
  • S. Pei et al.

    Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells

    J Biol Chem

    (2013)
  • L.S. Pike et al.

    Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells

    Biochim Biophys Acta

    (2011)
  • T. Robak et al.

    Current and emerging therapies for acute myeloid leukemia

    Clin Ther

    (2009)
  • L.A. Sauer et al.

    Mitochondrial malic enzymes. Mitochondrial NAD(P)+− dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas

    J Biol Chem

    (1980)
  • R. Scherz-Shouval et al.

    Regulation of autophagy by ROS: physiology and pathology

    Trends Biochem Sci

    (2011)
  • M.A. Selak et al.

    Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase

    Cancer Cell

    (2005)
  • M. Skrtic et al.

    Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia

    Cancer Cell

    (2011)
  • J.E. Sylvester et al.

    Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease

    Genet Med

    (2004)
  • J. Tamburini et al.

    Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia

    Blood

    (2009)
  • M.L. Torgersen et al.

    Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells

    Blood

    (2013)
  • J.W. Vardiman et al.

    The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes

    Blood

    (2009)
  • D.L. Vaux et al.

    Cell death in development

    Cell

    (1999)
  • P.S. Ward et al.

    The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate

    Cancer Cell

    (2010)
  • P.S. Ward et al.

    The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization

    J Biol Chem

    (2013)
  • L. Willems et al.

    Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia

    Blood

    (2013)
  • D.R. Wise et al.

    Glutamine addiction: a new therapeutic target in cancer

    Trends Biochem Sci

    (2010)
  • W. Xu et al.

    Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases

    Cancer Cell

    (2011)
  • J.K. Altman et al.

    Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting

    Clin Cancer Res

    (2014)
  • L. Bar-Peled et al.

    A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1

    Science

    (2013)
  • J. Boultwood et al.

    Amplification of mitochondrial DNA in acute myeloid leukaemia

    Br J Haematol

    (1996)
  • J. Cai et al.

    Mitochondrial redox signaling during apoptosis

    J Bioenerg Biomembr

    (1999)
  • N. Canh Hiep et al.

    Depletion of glutamine enhances sodium butyrate-induced erythroid differentiation of K562 cells

    J Biochem

    (2012)
  • A. Carracedo et al.

    Cancer metabolism: fatty acid oxidation in the limelight

    Nat Rev Cancer

    (2013)
  • A. Chatterjee et al.

    Mitochondrial DNA mutations in human cancer

    Oncogene

    (2006)
  • Z.X. Chen et al.

    Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells

    Cell Death Differ

    (2007)
  • A. Chiarugi et al.

    The NAD metabolome—a key determinant of cancer cell biology

    Nat Rev Cancer

    (2012)
  • L. Dang et al.

    Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

    Nature

    (2009)
  • R.J. DeBerardinis et al.

    Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer

    Oncogene

    (2010)
  • G. Del Poeta et al.

    Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia

    Curr Cancer Drug Targets

    (2008)
  • W.X. Ding et al.

    Mitophagy: mechanisms, pathophysiological roles, and analysis

    Biol Chem

    (2012)
  • M. Falkenberg et al.

    DNA replication and transcription in mammalian mitochondria

    Annu Rev Biochem

    (2007)
  • T. Finkel

    Signal transduction by reactive oxygen species

    J Cell Biol

    (2011)

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