IDH1 Mutation Is an Independent Inferior Prognostic Indicator for Patients with Myelodysplastic Syndromes

Wang, Na; Wang, Fei; Shan, Ning-ning; Sui, Xiaohui; Xu, Hui

doi:10.1159/000479546

Cited by 20 publications

(15 citation statements)

References 41 publications

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“…In multivariate analysis, IDH1 mutations but not IDH2 mutations were associated with shortened leukemia-free survival [ 22 ]. Wang et al confirmed these findings in a group of 97 MDSs showing that patients with IDH1 mutations displayed shorter overall and progression-free survival, whereas IDH2 mutations did not have impact on OS and PFS [ 23 ].…”

Section: Idh Mutations In Myelodysplastic Syndromesmentioning

confidence: 82%

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

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Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.

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Section: Idh Mutations In Myelodysplastic Syndromesmentioning

confidence: 82%

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Testa

Castelli

2020

Cancers

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“…DNMT3A mutations are more frequent in patients with AML (about 20%), whereas they are less common in patients with MDS (10%) . IDH1/2 (isocitrate deshydrogenase 1/2) mutations are closely associated with higher bone marrow blasts, lower neutrophil counts, and unspecific karyotypes . Mutant IDH1/2 can block myeloid differentiation and increase the accumulation of DNA damage in hematopoietic stem cell/myeloid progenitors leading to oncogenic transformation .…”

Section: Epigeneticsmentioning

confidence: 99%

“…IDH1/2 mutations vary from 4% to 12% in patients with MDS and are more common in AML . Furthermore, IDH1 mutations are an independent prognostic factor for patients with MDS . ASXL1 (addition of sex Combs‐like 1) and EZH2 (enhancer of zeste homolog 2) code for histone modifying enzymes and loss‐of‐function mutations are associated with poor survival in MDS.…”

Section: Epigeneticsmentioning

confidence: 99%

From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

Gadji

Pozzo

2018

Genes Chromosomes & Cancer

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Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability.

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“…2HG acts as a competitive inhibitor of α-ketoglutarate resulting in inhibition of multiple αKG-dependent dioxygenases including TET2. In addition, IDH1/IDH2 mutations are associated with global cytosine hypermethylation signatures that lead to impaired haematopoietic differentiation [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Common recurrent IDH mutations are located in codon 132 in exon 4 of the IDH1 gene and in codon 140 and codon 172 in exon 4 of the IDH2 gene. IDH1 encodes an enzyme that localizes to the cytosol and peroxisomes, while IDH2 encodes an enzyme that localizes to the mitochondria [7].…”

Section: Introductionmentioning

confidence: 99%

Study of Isocitrate Dehydrogenase 1and 2 Mutations in Adult Egyptian Patients with Denovo Acute Myeloblastic Leukemia, Their Relation to Clinical Characteristics, FLT3/ITD and Nucleophosmin 1 Mutations and Impact on Treatment Outcome

Barakat

Elsorady

Ayad

et al. 2019

IBRR

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Background: Acute myeloid leukaemia (AML) is a malignancy that is heterogeneous in nature characterized by genetic abnormalities some of which are established in the diagnosis and prognosis of the disease. An additional role for alterations in epigenetic mechanisms has been also highlighted in the pathogenesis of the disease. This may have a role in determining the disease outcome, impact the treatment decision and provide options for targeted therapies especially in patients who lack genetic aberrations. One of the modes of epigenetic dysregulation is mutation in genes encoding isocitrate dehydrogenase 1 and 2 that has been observed in AML with a higher incidence in patients with normal karyotype (NK). Aim of the work: The aim of this work was to study the frequency of IDH1 (R132) and IDH2 (R140Q, R172K) mutations in adult Egyptian patients with de novo acute myeloblastic leukemia (AML), their relation with clinical characteristics, other molecular markers (the internal tandem duplication (ITD)) mutation of FLT3 gene and NPM1 gene mutation) and impact on treatment outcome. Methods: Peripheral blood samples from 50 adult patients with denovo acute myeloid leukemia, admitted to the haematology unit at Alexandria Main University Hospital from February 2015 to February 2017, were used. The polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) was used for detection of IDH1 codon R132 and IDH2 codons (R140, R172) mutations on genomic DNA. PCR was used for detection of FLT3-ITD mutation on genomic DNA. PCR was used for detection of NPM1 mutation on RNA. Results: IDH 1and 2 mutations occurred in 30% of newly diagnosed AML patients and 47.6% of NK patients. Both mutations did not co-occur except in one case. IDH positive patients were significantly older than IDH negative patients (p=0.003). There was no statistically significant correlation between any of the clinical parameters and the IDH mutations. FAB-M2 was the most common FAB subtype among IDH positive patients. No correlation between IDH mutations and NPM1 or FLT3 could be demonstrated. IDH positive patients had significantly lower CR rates after induction chemotherapy than IDH negative patients (p=0.021). Conclusion: IDH1, 2 mutations are recurring genetic alterations in AML with a higher incidence in patients with normal karyotype and they may have an unfavorable impact on clinical outcome in adult AML patients.

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IDH1 Mutation Is an Independent Inferior Prognostic Indicator for Patients with Myelodysplastic Syndromes

Cited by 20 publications

References 41 publications

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

Study of Isocitrate Dehydrogenase 1and 2 Mutations in Adult Egyptian Patients with Denovo Acute Myeloblastic Leukemia, Their Relation to Clinical Characteristics, FLT3/ITD and Nucleophosmin 1 Mutations and Impact on Treatment Outcome

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