Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multi‐specific monoclonal antibody MsMab‐1

Liu, Xing; Kato, Yoshinori; Kaneko, Mika K.; Sugawara, Michio; Ogasawara, Satoshi; Tsujimoto, Yuta; Naganuma, Yasushi; Yamakawa, Mitsunori; Tsuchiya, Takashi; Takagi, Michiaki

doi:10.1002/cam4.149

Cited by 47 publications

(43 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies found IDH mutations in a variety of benign and malignant musculoskeletal tumors, including osteosarcomas and giant cell tumors of bone (16,31,32). Furthermore, the mouse mesenchymal cell line C3H10T1/2 expressing the IDH2 R172K mutation can give rise to poorly differentiated sarcomas in xenograft models (17).…”

Section: Discussionmentioning

confidence: 97%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

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

110

118

View full text Add to dashboard Cite

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.isocitrate dehydrogenase | cartilage tumor | hedgehog E nchondromas, one of the most common benign tumors occurring in bone, are present in more than 3% of the population (1, 2). They are composed of cells derived from chondrocytes and occur as solitary lesions or multiple lesions in enchondromatosis syndromes (Ollier disease or Maffucci syndrome-in the latter, enchondromas are associated with vascular malformations). Clinical problems caused by enchondromas include pain, fractures, and skeletal deformity. There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14). Disruption of this feedback loop can result in either skeletal dysplasias with abnormal bone growth or enchondromas; 5% of enchondromas harbor mutation in parathyroid hormone-like hormone receptor (PTHR1), resulting in activation of Hh signaling (6,(10)(11)(12)(13)(14), and expression of a mutant PTHR1 or overexpression of the Hh-regulated transcription factor Gli2 under the Col2a1 promoter causes enchondroma-like cartilage lesions to develop adjacent to the growth-plate ...

show abstract

Section: Discussionmentioning

confidence: 97%

Mutant IDH is sufficient to initiate enchondromatosis in mice

Hirata

Sato

Cairns

et al. 2015

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

110

118

View full text Add to dashboard Cite

show abstract

“…Mutations in IDH1 and IDH2 frequently occur in glioma (>75%) 96 and secondary glioblastoma (GBM) (70-75%) and are rarely detected in primary glioblastoma (5%). 97,98 Mutations in IDH1 and IDH2 have also been found in various human cancers with different frequencies, including acute myeloid leukemia (AML), 99 angioimmunoblastic T-cell lymphoma, 108 Most IDH1 and IDH2 mutations in cancers are often heterozygous with a wild-type allele, 96,97,109 and the mutations have been found to result in a neomorphic enzyme activity that converts a-ketoglutarate into the R-enantiomer of 2-hydroxyglutarate.…”

Section: Isocitrate Dehydrogenase (Idh)mentioning

confidence: 99%

Role of mitochondrial dysfunction in cancer progression

Hsu¹,

Tseng

Lee³

2016

Exp Biol Med (Maywood)

228

161

View full text Add to dashboard Cite

Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca 2þ , or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/ tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.

show abstract

“…Deep sequencing further revealed that mutated IDH1 and IDH2 occur in a high proportion (>70%) of low‐grade (grade II–III) astrocytomas and oligodendrogliomas and secondary glioblastoma 51, 52, 88, 89. Since these initial reports, mutations in IDH1 and IDH2 have also been found in other diverse cancers including 16–17% of patients with AML,53 20% of patients with angioimmunoblastic T‐cell lymphomas,90 and more rarely in cholangiocarcinomas,91 breast carcinomas,92 acute lymphoblastic leukemias,93 prostate cancer,93 osteosarcoma,94 and others 53, 91, 92, 93, 95, 96, 97. Interestingly, and unlike IDH mutations in glioma which are almost entirely in IDH1 , AML have been shown to exhibit an approximately equal frequency of IDH1 and IDH2 mutations 53, 54…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

View full text Add to dashboard Cite

Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

show abstract

Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multi‐specific monoclonal antibody MsMab‐1

Cited by 47 publications

References 35 publications

Mutant IDH is sufficient to initiate enchondromatosis in mice

Mutant IDH is sufficient to initiate enchondromatosis in mice

Role of mitochondrial dysfunction in cancer progression

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Contact Info

Product

Resources

About