A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders

Yoshida, Kenichi; Sanada, Masashi; Kato, Motohiro; Kawahata, Ryoichiro; Matsubara, Aiko; Takita, Jyunko; Ly, S.; Mori, Hiraku; Koeffler, H. Phillip; Ogawa, Seishi

doi:10.1038/leu.2010.241

Cited by 18 publications

(16 citation statements)

References 9 publications

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“…IDH1/IDH2 mutations are rare in MDS (4%-11%), but may be more common in sAML (8%-10%). [38][39][40] Patients with IDH1 mutations have inferior overall survival compared with nonmutated patients. 38 Heterozygous IDH1/IDH2 mutations result in the production of 2-hydroxyglutarate, which is dependent on the presence of the wild-type allele.…”

Section: Mutations In Regulators Of Dna Methylationmentioning

confidence: 99%

Genetics of Myelodysplastic Syndromes: New Insights

Graubert

Walter

2011

Hematology

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Myelodysplastic syndromes (MDS) are a heterogenous group of hematologic malignancies characterized by clonal expansion of BM myeloid cells with impaired differentiation. The identification of recurrent mutations in MDS samples has led to new insights into the pathophysiology of these disorders. Of particular interest is the recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are recurrently mutated in MDS, providing an important link between genetic and epigenetic alterations in this disease. The mechanism by which these mutated genes contribute to disease pathogenesis is an active area of research, with a current focus on which downstream target genes may be affected. Recent advances from sequencing studies suggest that multiple mutations are required for MDS initiation and progression to acute myeloid leukemia (AML). The past several years have yielded many new insights, but the complete genetic landscape of MDS is not yet known. Moreover, few (if any) of the findings are sufficiently robust to be incorporated into routine clinical practice at this time. Additional studies will be required to understand the prognostic implications of these mutations for treatment response, progression to AML, and survival.

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Section: Mutations In Regulators Of Dna Methylationmentioning

confidence: 99%

Genetics of Myelodysplastic Syndromes: New Insights

Graubert

Walter

2011

Hematology

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“…19 The mutational status of IDH1/2 in 71 of the 168 patients had been reported before. 13 TET2/IDH mutated cases were measured both at diagnosis of MDS and on progression to sAML by pyrosequencing and/or deep sequencing of the relevant mutant alleles. Pyrosequencing was performed as previously described.…”

Section: Analysis Of Gene Mutationsmentioning

confidence: 99%

“…Interestingly, it has been demonstrated that TET2 function is also compromised by 2-hydroxyglutarate, an oncogenic metabolite produced by gain-of-function mutations of isocitrate dehydrogenase (IDH) 1 and 2, which has been shown to occur mutually exclusive with regard to TET2 mutations in 3.5-12% of MDS patients. 5,8,[11][12][13][14][15][16] Until now, several studies carried out have addressed the clinical relevance of TET2 and IDH1/2 mutations in MDS. 4,6,8,[11][12][13] The prevalent view is that there is no significant impact of TET2 mutations on overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

“…The IDH1 but not IDH2 mutations were found to be associated with a higher risk of sAML transformation and poor prognosis in patients with MDS in one study, 11 whereas another study reported the opposite results showing no difference between patients with and without IDH1/2 mutations in terms of prognostic impact. 13 In the present study, we examined both TET2 and IDH mutations on a large cohort of de novo MDS patients from Taiwan and Japan. In particular, we investigated a large number of paired MDS/sAML samples (n=46) for mutational analysis to assess the role of TET2 and IDH1/2 mutations in the sAML evolution.…”

Section: Introductionmentioning

confidence: 99%

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Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

et al. 2013

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“…11,[88][89][90] Mutations in IDH1 and IDH2 are uncommon in MDS (rates of approximately 4%-11%), but appear to be more prevalent in secondary AML (8%-10%). [91][92][93] TET2, IDH1, and IDH2 mutations are mutually exclusive as both are linked to abnormal DNA hydroxymethylation. 94 Finally, mutations in the histone regulator EZH2 are present in approximately 2% to 6% of patients with MDS, in addition to rare mutations and deletions of KDM6A.…”

Section: Myelodysplastic Syndromes and Mds/mpn Overlap Disordersmentioning

confidence: 99%

Molecular Genetic Biomarkers in Myeloid Malignancies

Matynia

Szankasi

Shen³

et al. 2014

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Recent studies using massively parallel sequencing technologies, so-called next-generation sequencing, have uncovered numerous recurrent, single-gene variants or mutations across the spectrum of myeloid malignancies.Objectives.-To review the recent advances in the understanding of the molecular basis of myeloid neoplasms, including their significance for diagnostic and prognostic purposes and the possible implications for the development of novel therapeutic strategies.Data Sources.-Literature review.Conclusions.-The recurrent mutations found in myeloid malignancies fall into distinct functional categories.These include (1) cell signaling factors, (2) transcription factors, (3) regulators of the cell cycle, (4) regulators of DNA methylation, (5) regulators of histone modification, (6) RNA-splicing factors, and (7) components of the cohesin complex. As the clinical significance of these mutations and mutation combinations is established, testing for their presence is likely to become a routine part of the diagnostic workup. This review will attempt to establish a framework for understanding these mutations in the context of myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia.

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A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders

Cited by 18 publications

References 9 publications

Genetics of Myelodysplastic Syndromes: New Insights

Genetics of Myelodysplastic Syndromes: New Insights

Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

Molecular Genetic Biomarkers in Myeloid Malignancies

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