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Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL.

ABSTRACT: IDH1 and IDH2 mutations (IDH1/2^Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2^Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2^Mut. Mutational patterns of IDH1/2^Mut in T-ALL present some specific features compared to AML. Whereas IDH2^R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2^R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2^Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

SUBMITTER: Simonin M

PROVIDER: S-EPMC8091755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives.

Project description:Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of ?-ketoglutarate (?-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to ?-KG, and acts as an ?-KG antagonist to competitively inhibit multiple ?-KG-dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets.

| S-EPMC3897211 | biostudies-other

IDH1 and IDH2 mutations in gliomas.

Project description:BackgroundA recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).MethodsWe determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.ResultsWe identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.ConclusionsMutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

| S-EPMC2820383 | biostudies-literature

IDH1 and IDH2 mutations in pediatric acute leukemia.

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Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms.

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| S-EPMC5821256 | biostudies-literature

Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma.

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| S-EPMC3100313 | biostudies-literature

Acute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm.

Project description:Acute myeloid leukemia is a genetically heterogeneous hematologic malignancy; approximately 20% of AML harbors a mutation in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2. These recurrent mutations in key metabolic enzymes lead to the production of the oncometabolite 2-hydroxyglutarate, which promotes leukemogenesis through a block in normal myeloid differentiation. Since this discovery, selective oral inhibitors of mutant IDH1 and IDH2 have subsequently been developed and are now approved as single agent therapy, based on clinical efficacy observed within the original first-in-human trials. The investigation of IDH inhibitors in combination with standard therapies such as azacytidine, with intensive chemotherapy, and with other small molecule targeted therapies in rational combinations are currently under evaluation to further improve upon clinical efficacy.

| S-EPMC8175383 | biostudies-literature

IDH1 and IDH2 mutations in lung adenocarcinomas: Evidences of subclonal evolution.

Project description:BackgroundSelective IDH1 and IDH2 inhibitors have been approved for targeted therapy of acute myeloid leukemia. Clinical trials for solid tumors with IDH1 and IDH2 (IDH1/2) mutations are ongoing. Reports of IDH1/2-mutated non-small cell lung cancers (NSCLCs), however, are limited.MethodsWe evaluated IDH1/2 mutations in 1,924 NSCLC specimens (92% adenocarcinoma) using a next-generation sequencing assay.ResultsRetrospective quality assessments identified false detection of IDH1 c.395G>A (p.R132H) resulting from cytosine deamination (C:G→T:A) artifact in one specimen. IDH1/2 mutations were detected in 9 (0.5%) adenocarcinomas taken by fine-needle aspiration (n = 3), thoracentesis (n = 2) or core biopsy (n = 4). All nine adenocarcinomas showed high-grade features. Extensive clear cell change, however, was not observed. High expression (50% or greater) of PD-L1 was observed in two of five specimens examined. IDH1/2 mutations were associated with old age, smoking history, and coexisting KRAS mutation. Lower than expected variant allele frequency of IDH1/2 mutants and coexistence of IDH1/2 mutations with known trunk drivers in the BRAF, EGFR, and KRAS genes suggest they could be branching drivers leading to subclonal evolution in lung adenocarcinomas. Multiregional analysis of an adenocarcinoma harboring two IDH2 mutations revealed parallel evolution originating from a KRAS-mutated lineage, further supporting subclonal evolution promoted by IDH1/2 mutations.ConclusionsIDH1/2 mutations in NSCLCs are uncommon. They occur in adenocarcinomas with high-grade features and may be branching drivers leading to subclonal evolution. Accumulation of more IDH1/2-mutated NSCLCs is needed to clarify their clinicopathological characteristics and implications for targeted therapy.

| S-EPMC7300411 | biostudies-literature

IDH1/IDH2 but not TP53 mutations predict prognosis in Bulgarian glioblastoma patients.

Project description:Mutations in genes encoding isocitrate dehydrogenase isoforms 1 (IDH1) and 2 (IDH2) have been associated with good prognosis for patients with brain neoplasias and have been commonly found together with mutated TP53 gene. To determine the prevalence of IDH1, IDH2, and TP53 mutations and their impact on overall survival 106 glioblastoma patients were analysed. IDH1 mutations were detected in 13 and IDH2 mutation in one patient. Two homozygous samples with R132H mutation in IDH1 gene and a novel aberration K129R in IDH2 gene were found. Sixty-four percent of IDH1/IDH2 mutated tumours harboured also a mutation in TP53 gene. Genetic aberrations in TP53 were present in 37 patients. Statistical analysis of the impact of the studied factors on the overall survival showed that the mutations in IDH1/IDH2, but not the ones in TP53, were associated with longer survival. Also, the impact of age on prognosis was confirmed. This is the first comprehensive study on glioblastomas in Bulgaria. Our results suggest that IDH1/IDH2 but not TP53 mutations together with other prognostic factors such as age might be applied in clinical practice for prediction of outcome in patients with glioblastomas.

| S-EPMC4017788 | biostudies-literature

Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma.

Project description:The mutant IDH1 inhibitor ivosidenib improves outcomes for patients with IDH1-mutated cholangiocarcinoma, but resistance inevitably develops. Mechanisms of resistance and strategies to overcome resistance are poorly understood. Here we describe two patients with IDH1 R132C-mutated metastatic cholangiocarcinoma who developed acquired resistance to ivosidenib. After disease progression, one patient developed an oncogenic IDH2 mutation, and the second patient acquired a secondary IDH1 D279N mutation. To characterize the putative IDH1 resistance mutation, cells expressing the double-mutant were generated. In vitro, IDH1 R132H/D279N produces (R)-2HG less efficiently than IDH1 R132H. However, its binding to ivosidenib is impaired and it retains the ability to produce (R)-2HG and promote cellular transformation in the presence of ivosidenib. The irreversible mutant IDH1 inhibitor LY3410738 binds and blocks (R)-2HG production and cellular transformation by IDH1 R132H/D279N. These resistance mechanisms suggest that IDH1-mutated cholangiocarcinomas remain dependent on (R)-2HG even after prolonged ivosidenib treatment. Sequential mutant IDH inhibitor therapy should be explored as a strategy to overcome acquired resistance to mutant IDH inhibitors.

| S-EPMC9440204 | biostudies-literature

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