D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

Akbay, Esra A.; Moslehi, Javid; Christensen, Camilla L.; Saha, Supriya K.; Tchaicha, Jeremy H.; Ramkissoon, Shakti; Stewart, Kelly M.; Carretero, Julián; Kikuchi, Eiki; Zhang, Haikuo; Cohoon, Travis J.; Murray, Stuart; Liu, Wei; Uno, Kazumasa; Fisch, Sudeshna; Jones, Kristen L.; Gurumurthy, Sushma; Gliser, Camelia; Choe, Sung; Keenan, Marie C.; Son, Jaekyoung; Stanley, Illana A.; Losman, Julie A.; Padera, Robert F.; Bronson, Roderick T.; Asara, John M.; Abdel-Wahab, Omar; Amrein, Philip C.; Fathi, Amir T.; Danial, Nika N.; Kimmelman, Alec C.; Kung, Andrew L.; Ligon, Keith L.; Yen, Katharine; Kaelin, William G.; Bardeesy, Nabeel; Wong, Kwok-Kin

doi:10.1101/gad.231233.113

Cited by 77 publications

(76 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…S1C). A previous report indicated that overproduction of D2-HG, caused by a broadly expressed mutant IDH2, is associated with cardiac hypertrophy, dilatation, and failure (8). We found no cardiac hypertrophy in transplanted mice with Idh2…”

Section: Significancesupporting

confidence: 43%

“…To understand whether overproduction of D2-HG alone was responsible for the effects observed in the Idh2 mutant mouse model, we measured rates of substrate metabolism in the isolated working rat heart and conducted computational flux rate analysis using the CardioNet model of mammalian cardiac metabolism (14). Rat hearts were perfused ex vivo in the presence or absence of D2-HG in concentrations similar to those found in the plasma of Idh2 R140Q mutant mice (0.5 mM) and AML patients (8,(15)(16)(17) and those reported by Latini et al (18) to promote inhibition of ATP synthase in cardiac muscle in vitro (range 0.05-5 mM; F 0 /F 1 ATP synthase K i = 0.47 ± 0.18 mM) (Fig. 1A).…”

Section: Significancementioning

confidence: 99%

“…Other recent reports suggest that systemically produced D2-HG by neomorphic IDH2 is associated with cardiomyopathy, suggesting that D2-HG influences cardiac cellular responses (8,9). However, the extent to which D2-HG can directly affect cardiac function and metabolism, and which processes are involved, has remained unknown.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Oncometabolite d -2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

Karlstaedt

Zhang

Vitrac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

112

View full text Add to dashboard Cite

Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite D-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart. This contractile dysfunction is associated with impaired oxidative decarboxylation of α-ketoglutarate, a redirection of Krebs cycle intermediates, and increased ATP citrate lyase (ACL) activity. Increased availability of D2-HG also leads to altered histone methylation and acetylation in the heart. We propose that D2-HG promotes cardiac dysfunction by impairing α-ketoglutarate dehydrogenase and induces histone modifications in an ACL-dependent manner. Collectively, our results highlight the impact of cancer cell metabolism on function and metabolism of the heart. D-2-hydroxyglutarate | IDH2 | metabolism | cardiomyopathy | flux rate analysis M etabolic dysregulation in cancer cells changes the way nutrients are consumed and macromolecules are produced to meet the increased demands for cell growth. Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are common and are described in several cancer types (i.e., gliomas and acute myeloid leukemia). IDH mutations lead to increased production and accumulation of the oncometabolite D-2-hydroxyglutarate (D2-HG) through a neomorphic enzymatic function (1). WT IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), while reducing NADP + to NADPH either in the cytosol and peroxisome (IDH1), or in mitochondria (IDH2). In this reaction, D2-HG is produced in small amounts but converted back to its structural homolog α-KG by D2-HG dehydrogenase. Common features of tumors with IDH1/2 mutations are abnormal histone and DNA methylation, connecting metabolic changes with epigenetic control of gene expression (2). In hematologic malignancies, IDH1/2 are often co-mutated with epigenetic regulatory genes encoding enzymes that are important in DNA hydroxymethylation (i.e., tet methylcytosine dioxygenase 2, TET2) and methylation (i.e., DNA methyltransferase 3 A, DNMT3A) (3). Accumulation of D2-HG contributes to leukemogenesis, likely due to inhibition of α-KG-dependent dioxygenases, including histone lysine demethylases (KDMs) and TET2 (4). This hypothesis has been supported by recent reports linking the hypermethylation phenotype in cancer cells to IDH, fumarate hydratase, and succinate dehydrogenase mutations (5, 6).The starting point for the present work were reports that myeloid malignancies are associated with cardiac pathologies, which are commonly considered a side effect of chemotherapy (7). Other recent reports suggest that systemically produced D2-HG by neomorphic ...

show abstract

Section: Significancesupporting

confidence: 43%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Oncometabolite d -2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

Karlstaedt

Zhang

Vitrac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

112

View full text Add to dashboard Cite

show abstract

“…Immunohistochemistry was performed using anti-CD138, anti–Ki-67, and anti–c-Myc, as previously reported (37). …”

Section: Methodsmentioning

confidence: 99%

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

et al. 2017

View full text Add to dashboard Cite

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.

show abstract

“…5,14,[18][19][20] Targeting mutant IDH1 or IDH2 to the mouse central nervous system (CNS) results in neurodegeneration or perturbed basement membrane function, without evidence yet that it can drive tumorigenesis in the CNS. 14,21 IDH mutations are being pursued as therapeutic targets. 10,[22][23][24] However, the mechanisms by which IDH mutants contribute to cancer pathogenesis remain only partially understood.…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Reitman

Sinenko

Spana

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• Homologs to cancer-derived IDH1 and IDH2 mutants produce D-2HG and drive expansion of Drosophila blood cells. • In flies, mutant Idh interactswith genes that regulate reduced nicotinamide adenine dinucleotide phosphate, reactive oxygen species, and apoptosis.Gain-of-function mutations in nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase (IDH)1 and IDH2 frequently arise in human leukemias and other cancers and produce high levels of D-2-hydroxyglutarate (D-2HG). We expressed the R195H mutant of Drosophila Idh (CG7176), which is equivalent to the human cancerassociated IDH1-R132H mutant, in fly tissues using the UAS-Gal4 binary expression system. Idh-R195H caused a >25-fold elevation of D-2HG when expressed ubiquitously in flies. Expression of mutant Idh in larval blood cells (hemocytes) resulted in higher numbers of circulating blood cells. Mutant Idh expression in fly neurons resulted in neurologic and wing-expansion defects, and these phenotypes were rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators. Idh-R163Q, which is homologous to the common leukemia-associated IDH2-R140Q mutant, resulted in moderately elevated D-2HG and milder phenotypes. We identified the fly homolog of D-2-hydroxyglutaric acid dehydrogenase (CG3835), which metabolizes D-2HG, and showed that coexpression of this enzyme with mutant Idh abolishes mutant Idh-associated phenotypes. These results provide a flexible model system to interrogate a cancer-related genetic and metabolic pathway and offer insights into the impact of IDH mutation and D-2HG on metazoan tissues. (Blood. 2015;125(2):336-345) Introduction Somatic, gain-of-function mutations in nicotinamide adenine dinucleotide phosphate (NADP 1 )-dependent isocitrate dehydrogenase (IDH)1 and IDH2 occur frequently in acute myeloid leukemias, myelodysplastic syndromes, angioimmunoblastic T-cell lymphomas, brain tumors, and other cancers. [1][2][3][4][5][6][7][8][9] The mutations occur at the conserved active-site residues of Arg132 in IDH1, or Arg140 and Arg172 in IDH2. When mutated, IDH1 and IDH2 lose their normal function to convert isocitrate to a-ketoglutarate and acquire a gain of function to convert a-ketoglutarate to D-2-hydroxyglutarate (D-2HG).10 D-2HG accumulates to ;100-fold higher levels in IDHmutated cancer tissues.10,11 D-2HG inhibits Fe(II)-a-ketoglutaratedependent dioxygenases, including histone demethylases, DNA hydroxymethyltransferases, and collagen proline hydroxylases. 12,13 Inhibition of these dioxygenase enzymes leads to histone lysine hypermethylation, DNA hypermethylation, and collagen dysfunction in mammalian tissues expressing mutated IDH1 or IDH2. 5,[14][15][16] IDH mutations can also sensitize cells to reactive oxygen species (ROS) induction, possibly because mutant IDH consumes reduced NADP (NADPH), a cofactor important for scavenging intracellular ROS. 17 Targeting mutated IDH1 or IDH2 to mouse hematopoietic progenitors results in an increased number of these progeni...

show abstract

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

Cited by 77 publications

References 52 publications

Oncometabolite d -2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

Oncometabolite d -2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Contact Info

Product

Resources

About