Enigmas of IDH mutations in hematology/oncology

Heuser, Michael; Cruz, Michelle; Goparaju, Ramya; Chaturvedi, Anuhar

doi:10.1016/j.exphem.2015.05.005

Cited by 23 publications

(17 citation statements)

References 115 publications

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“…IDH1/2 pathogenic mutations were often found to co‐exist with mutations affecting other oncogenic pathways. Studies on IDH1/2‐ mutated gliomas give a notion that the glial cells may become susceptible to mutant IDH1 through activation of MAPK, PI3K/Akt, and MYC, and loss of p53 signalling . We hypothesize that the concurrent genetic alterations in IDH2 ‐mutated sinonasal carcinomas may collaborate with mutant IDH2 to induce and promote carcinogenesis in these tumours.…”

Section: Resultsmentioning

confidence: 94%

Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

et al. 2017

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Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphologic spectrum of 47 sinonasal tumors including 17 (36.2%) SNUCs were analyzed at genomic level. Thirty carcinomas (Cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT™) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumors (Cohort 2) were examined only for presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in 2 (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of 2 high-grade neuroendocrine carcinomas, large cell type (HGNEC). No IDH2 mutation was detected in any of 5 olfactory neuroblastomas or in any of 5 SMARCB1–deficient carcinomas. Among 12 IDH2-mutated cases in Cohort 1, 5 (41.7%) harbored co-existing TP53 mutations, 4 (33.3%) CDKN2A/2B loss-of-function alterations, 4 (33.3%) MYC amplification, and 3 (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2-mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly differentiated sinonasal carcinomas may be amenable to IDH2-targeted therapy.

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Section: Resultsmentioning

confidence: 94%

Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

et al. 2017

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“…9,10 2-HG accumulation inhibits multiple α-KG-dependent dioxygenases, including histone and DNA demethylases, which regulate cellular epigenetic state. 11 The first-in-human phase I clinical study of the novel, oral mutant IDH1 inhibitor, AG-120, is ongoing (ClinicalTrials.gov NCT02074839), and early results in 66 patients indicate that monotherapy is well tolerated, with an overall response rate of 36% by International Working Group (IWG) criteria in a primarily relapsed/refractory AML population. 12 Responses occur without a period of bone marrow aplasia, unlike standard cytoreductive therapy.…”

Section: Introductionmentioning

confidence: 99%

Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120

Birendra

DiNardo

2016

Clinical Lymphoma Myeloma and Leukemia

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We describe 3 patients with relapsed/refractory acute myeloid leukemia who developed clinically-apparent differentiation concurrent with clinical response during monotherapy with AG-120, a novel, oral inhibitor of mutant isocitrate dehydrogenase 1. Symptoms included marked leukocytosis and exuberant neutrophil recovery among other clinically-apparent constitutional manifestations. Awareness of the potential for differentiation syndrome with such inhibitors, and prompt identification and intervention, are essential to facilitate clinical resolution. Background Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described. Patients and Methods We describe 3 patients who developed clinically apparent DS while on monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML. Results AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same timeframe as clinical response, strengthening the purported mechanism of targeted mutant IDH-inhibitor therapy via successful myeloid maturation. Symptoms of DS were non-specific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis. Conclusion DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients may present with non-specific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.

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“…In this prediction, should act against Warburg glycolytic phenotype and other HIF-mediated transcription changes. However, PHDs exhibit also an important HIF-independent fuel-sensing regulation, which may have an opposite role (Duran et al 2013, Heuser et al 2015.…”

Section: R-2hgmentioning

confidence: 99%

“…The neomorphic activity of mutated IDH1 or IDH2 enzymes probably causes epigenetic changes which in turn lead to a dramatic elevation of 2HG levels. Such levels themselves are sufficient to promote leukemogenesis in the hematopoietic cells through the maintenance of de-differentiation and increased proliferation (Heuser et al 2015, Losman et al 2013, Wang et al 2015. Also, a key component of hypoxia-inducible factor (HIF) regulation pathway, the prolyl hydroxylase domain-2 (PHD2/EglN1) enzyme has been found to be activated by R-2HG (Koivunen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Background Levels of Neomorphic 2-hydroxyglutarate Facilitate Proliferation of Primary Fibroblasts

Dvořák

Zelenka²,

Smolková³

et al. 2017

Physiol Res

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Each cell types or tissues contain certain “physiological” levels of R-2-hydroxyglutarate (2HG), as well as enzymes for its synthesis and degradation. 2HG accumulates in certain tumors, possessing heterozygous point mutations of isocitrate dehydrogenases IDH1 (cytosolic) or IDH2 (mitochondrial) and contributes to strengthening their malignancy by inhibiting 2-oxoglutarate-dependent dioxygenases. By blocking histone de-methylation and 5-methyl-cytosine hydroxylation, 2HG maintains cancer cells de-differentiated and promotes their proliferation. However, physiological 2HG formation and formation by non-mutant IDH1/2 in cancer cells were neglected. Consequently, low levels of 2HG might play certain physiological roles. We aimed to elucidate this issue and found that compared to highest 2HG levels in hepatocellular carcinoma HepG2 cells and moderate levels in neuroblastoma SH-SY5Y cells, rat primary fibroblast contained low basal 2HG levels at early passages. These levels increased at late passage and likewise 2HG/2OG ratios dropped without growth factors and enormously increased at hypoxia, reaching levels compared to cancer HepG2 cells. Responses in SH-SY5Y cells were opposite. Moreover, external 2HG supplementation enhanced fibroblast growth. Hence, we conclude that low 2HG levels facilitate cell proliferation in primary fibroblasts, acting via hypoxia-induced factor regulations and epigenetic changes.

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Enigmas of IDH mutations in hematology/oncology

Cited by 23 publications

References 115 publications

Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120

Background Levels of Neomorphic 2-hydroxyglutarate Facilitate Proliferation of Primary Fibroblasts

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