Isocitrate dehydrogenase mutations in leukemia

McKenney, Anna Sophia; Levine, Ross L.

doi:10.1172/jci67266

Cited by 65 publications

(40 citation statements)

References 73 publications

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“…A promising area is the ongoing development of small molecule inhibitors of mutant isocitrate dehydrogenase (IDH) isoforms, including IDH2 that localizes to mitochondria. Gain-of-function IDH mutations identified in gliomas (40), acute myelogenous leukemias (AML) (41), and perhaps operative in other cancer types, promote the accumulation of 2-hydroxyglutarate (2-HG). This is an oncometabolite that deregulates chromatin remodeling enzymes, resulting in epigenetic silencing of tumor suppressor loci and differentiation block in AML (34).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

Caino

Altieri

2016

Clinical Cancer Research

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Small molecule inhibitors of the phosphatidylinositol 3-kinase (PI3K), Akt and mTOR pathway currently in the clinic produce a paradoxical reactivation of the pathway they are intended to suppress. Furthermore, fresh experimental evidence with PI3K antagonists in melanoma, glioblastoma and prostate cancer shows that mitochondrial metabolism drives an elaborate process of tumor adaptation culminating with drug resistance and metastatic competency. This is centered on reprogramming of mitochondrial functions to promote improved cell survival and to fuel the machinery of cell motility and invasion. Key players in these responses are molecular chaperones of the Heat Shock Protein 90 (Hsp90) family compartmentalized in mitochondria, which suppress apoptosis via phosphorylation of the pore component, Cyclophilin D, and enable the subcellular repositioning of active mitochondria to membrane protrusions implicated in cell motility. An inhibitor of mitochondrial Hsp90s in preclinical development (Gamitrinib) prevents adaptive mitochondrial reprogramming and shows potent anti-tumor activity in vitro and in vivo. Other therapeutic strategies to target mitochondria for cancer therapy include small molecule inhibitors of mutant isocitrate dehydrogenase (IDH) IDH1 (AG-120) and IDH2 (AG-221) which opened new therapeutic prospects for high-risk AML patients. A second approach of mitochondrial therapeutics focuses on agents that elevate toxic ROS levels from a leaky electron transport chain, nevertheless the clinical experience with these compounds, including a quinone derivative, ARQ 501, and a copper chelator, elesclomol (STA-4783) is limited. In light of these evidences, we discuss how best to target a resurgence of mitochondrial bioenergetics for cancer therapy.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

Caino

Altieri

2016

Clinical Cancer Research

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“…First, based on results from unsupervised statistical inspection, we decided to pool BM samples with the respective PB and observed that despite the small number of cases, supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) allowed clustering of the samples at diagnosis (tp1 H ) according to the presence or absence of mutations in IDH genes (Fig. 1d, e), supporting the notion that these mutations have an overall impact on the metabolome [2, 3]. Moreover, OPLS-DA discriminated the metabolic differences between patients at disease diagnosis and those in remission (tp5 H and tp9 H ), highlighting 30 metabolites significantly contributing to the model (Fig.…”

mentioning

confidence: 88%

“…Acute myeloid leukemia (AML) permits analysis of the impact of a systemic cancer on the metabolism over time. Oncometabolites have been demonstrated in 5–20 % of AML-harboring mutations in Isocitrate Dehydrogenase (IDH) genes [2, 3], and the metabolic profile of AML cell lines can be employed to investigate drug treatments [4, 5]. Moreover, previous studies linked AML with perturbation of metabolic pathways including glucose metabolism [6, 7].…”

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confidence: 99%

Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

Carrabba¹,

Tavel²,

Oliveira³

et al. 2016

J Hematol Oncol

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Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML), new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other “-omics” disciplines, holds promise in identifying disease-specific and clinically relevant features.In this study, we took advantage of nuclear magnetic resonance (NMR) to trace AML-associated metabolic trajectory employing two complementary strategies. On the one hand, we performed a prospective observational clinical trial to identify metabolic changes associated with blast clearance during the first two cycles of intensive chemotherapy in nine adult patients. On the other hand, to reduce the intrinsic variability associated with human samples and AML genetic heterogeneity, we analyzed the metabolic changes in the plasma of immunocompromised mice upon engraftment of primary human AML blasts.Combining the two longitudinal approaches, we narrowed our screen to seven common metabolites, for which we observed a mirror-like trajectory in mice and humans, tracing AML progression and remission, respectively. We interpreted this set of metabolites as a dynamic fingerprint of AML evolution.Overall, these NMR-based metabolomic data, to be consolidated in larger cohorts and integrated in more comprehensive system biology approaches, hold promise for providing valuable and non-redundant information on the systemic effects of leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0346-2) contains supplementary material, which is available to authorized users.

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“…An important theme is emerging whereby metabolism can have a major influence on the epigenetic state (57). The McKenney and Levine Review discusses the clinical aspects of IDH-mutant acute myeloid leukemia and the relationship between altered metabolism and epigenetic changes that impair differentiation in malignant cells (58). Magnetic resonance spectroscopy is a way to noninvasively image metabolites and could be a solution to the challenge of tracking metabolism in patient tumors.…”

Section: Challenges To Developing Drugs Targeting Cancer Metabolismmentioning

confidence: 99%

Exploiting tumor metabolism: challenges for clinical translation

Heiden¹

2013

J. Clin. Invest.

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The metabolism of cancer cells differs from most normal cells, but how to exploit this difference for patient benefit is incompletely understood. Cancer cells require altered metabolism to efficiently incorporate nutrients into biomass and support abnormal proliferation. In addition, the survival of tumor cells outside of a normal tissue context requires adaptation of metabolism to different microenvironments. Some existing chemotherapies target metabolic enzymes, and there is a resurgent interest in developing new cancer drugs that interfere with metabolism. Success with this approach depends on understanding why specific metabolic pathways are important for cancer cells, determining how best to select patients, and developing technologies for monitoring patient response to therapies that target metabolic enzymes. The articles in this Review series address these issues, with a focus on how altered metabolism might influence tumor progression and how this knowledge might inform the use of new therapies targeting cancer metabolism. Emerging biomarker strategies to guide drug development are also highlighted.

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Isocitrate dehydrogenase mutations in leukemia

Cited by 65 publications

References 73 publications

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

Exploiting tumor metabolism: challenges for clinical translation

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