Whole‐exome sequencing detects somatic mutations of <i>IDH1</i> in metaphyseal chondromatosis with <scp>D</scp>‐2‐hydroxyglutaric aciduria (MC‐HGA)

Vissers, Lisenka E.L.M.; Fano, Virginia; Diego, Martinelli; Campos‐Xavier, Belinda; Barbuti, Domenico; Cho, Tae Joon; Dursun, Ahmet; Kim, Ok Hwa; Lee, Sun Hee; Timpani, Giuseppina; Nishimura, Gen; Unger, Sheila; Sass, Jörn Oliver; Veltman, Joris A.; Brunner, Han G.; Bonafé, Luisa; Dionisi‐Vici, Carlo; Superti‐Furga, Andrea

doi:10.1002/ajmg.a.34325

Cited by 48 publications

(35 citation statements)

References 18 publications

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“…78,79 We developed this Drosophila model to enable rapid in vivo assays to identify genetic interactions with mutant IDH, in order to map the molecular pathways by which mutant IDH exerts biological phenotypes and to discover therapeutic susceptibilities of IDHmutated cancer tissues. We used this system to test whether a focused panel of candidate genes interacted with mutant IDH in the fly.…”

Section: Discussionmentioning

confidence: 99%

“…77 Germline IDH1-R132H mutation has been speculated to be incompatible with human development because it has only been observed in a mosaic distribution, and even then it is associated with severe metaphysical chondromatosis and D-2-hydroxyglutaric aciduria. 78,79 We developed this Drosophila model to enable rapid in vivo assays to identify genetic interactions with mutant IDH, in order to map the molecular pathways by which mutant IDH exerts biological phenotypes and to discover therapeutic susceptibilities of IDHmutated cancer tissues. We used this system to test whether a focused panel of candidate genes interacted with mutant IDH in the fly.…”

Section: Discussionmentioning

confidence: 99%

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

Reitman

Sinenko

Spana

et al. 2015

Blood

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Reitman

Sinenko

Spana

et al. 2015

Blood

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“…96 In a related arena, the HIF signalling pathway is potentially involved in the initiation and progression of human chondrosarcomas. [97][98] Mutations that affect isocitrate dehydrogenases 1 and 2 occur in human chondrosarcomas, [97][98] and lead to depletion of the co-factor α-ketoglutarate-which, in turn, could lead to increased accumulation of HIFs through inhibition of HIF prolyl hydroxylases. 99 The HIF signalling pathway might, therefore, be altered in chrondrosarcomas, which could contribute, at least in part, to the initiation and/or progression of these malignancies.…”

Section: [H2] Metastasis To Bonementioning

confidence: 99%

Hypoxia-driven pathways in bone development, regeneration and disease

2012

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Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxiainducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have identified important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor-A (VEGF)-a potent angiogenic factor and a downstream target of the HIF pathway-in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and haematopoiesis, and pay particular attention to the complex relationship between HIF and VEGF in these tissues based on data collected in animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF. This knowledge can also be relevant for diseases like cancer and ischemia.

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“…To detect somatic mutations in cancer, Yan et al and Vissers et al [169,170] usually compare tumour vs normal samples for the same individual.…”

Section: Box 11: Somatic Vs Germline Mutationsmentioning

confidence: 99%

Computational Errors and Biases in Short Read Next Generation Sequencing

Abnizova¹,

Boekhorst²,

Orlov³

2017

J Proteomics Bioinform

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Whole‐exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D‐2‐hydroxyglutaric aciduria (MC‐HGA)

Cited by 48 publications

References 18 publications

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

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

Hypoxia-driven pathways in bone development, regeneration and disease

Computational Errors and Biases in Short Read Next Generation Sequencing

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