Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C > T have a prognostic value in acute myeloid leukemia

Abstract

BackgroundThe isocitrate dehydrogenase (IDH1/IDH2) genes are metabolic enzymes, which are frequently mutated in acute myeloid leukemia (AML). The enzymes acquire neomorphic enzymatic activity when they mutated.MethodsWe have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP 105C > T (rs11554137) in 189 unselected de novo AML patients by polymerase chain reaction amplification followed by direct sequencing. The survival are presented in Kaplan Meier curves with log rank test. Multivariable survival analysis was conducted using Cox regression method, taking age, risk group, treatment, IDH1/2 mutations and IDH1 SNP105 genotype into account.ResultsOverall, IDH1/2 mutations were found in 41/187 (21.7%) of the AML patients. IDH1 codon 132 mutations were present in 7.9%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 11.1% and 2.6%, respectively. The SNP 105C > T was present in 10.5% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p < 0.001) was observed in the intermediate risk patient group. Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative AML patients (p = 0.004).ConclusionsOur results indicate that AML-patients with IDH2 mutations or the IDH1 SNP 105C > T variant can represent a new subgroup for risk stratification and may indicate new treatment options.

Prognostic implications of IDH1rs11554137 and IDH2R140Q SNPs mutations in cytogenetically normal acute myeloid leukemia

“…These discrepancies can be attributed to variable inclusion criteria of the studied sample, ethnic variability, sample size, and variable detection assays sensitivity. As previously reported, all our patients with positive IDH1/2 SNP mutations were heterozygous [18,19]. Moreover, only one patient harbored both mutations, in accordance with Saadi and his fellows, suggesting that these mutations are mutually exclusive [20].…”

Durable remissions with venetoclax monotherapy in secondary AML refractory to hypomethylating agents and high expression of BCL‐2 and/or BIM

“…Therapy response was evaluated by the revised International Working Group (IWG) criteria . Primers for isocitrate dehydrogenase (IDH) 1 and 2 exon 4 analysis and PCR conditions were used as previously described . Immunohistochemical staining was performed in myeloblasts based on pretreatment bone marrow aspirates/biopsies, which had been obtained during routine clinical care, using a Bond RXm system (Leica, Wetzlar) with primary antibodies against BCL‐2 (M0887, DAKO, Agilent, Santa Clara, CA), BIM (ADI‐AAP‐330, Enzo Life Sciences, Farmingdale, NY), and MCL‐1 (16225‐1‐AP, Rosemont, IL).…”

“…16 Primers for isocitrate dehydrogenase (IDH) 1 and 2 exon 4 analysis and PCR conditions were used as previously described. 17 Immunohistochemical staining was performed in myeloblasts based on pretreatment bone marrow aspirates/biopsies, which had been obtained during routine clinical care, using a Bond RXm system (Leica, Wetzlar) with primary antibodies against BCL-2 (M0887, DAKO, Agilent, Santa Clara, CA), BIM (ADI-AAP-330, Enzo Life Sciences, Farmingdale, NY), and MCL-1 (16225-1-AP, Rosemont, IL). Briefly, slides were deparaffinized using deparaffinization solution, pretreated with epitope retrieval solution 1 (corresponding to citrate buffer pH6) for 50 or 30 minutes, for MCL-1 and BCL-2, respectively, or epitope retrieval solution 2 (corresponding to EDTA buffer pH8) for 30 minutes for BIM.…”

Identification of driver and subclonal mutations in ASXL1 and IDH1/IDH2 genes in an Argentine series of patients with myelofibrosis

“…However, the synonym variant IDH1 c.315 C>T (p.G105=) could be identified in 4 patients (4/39, 10.2%) in a heterozygous state with a minor allele frequency of 0.051 (4 alleles of 78), similar to the registered in the 1000 Genomes Project database (rs11554137).This variant is predicted as pathogenic (score: 0.85) by the FATHMM algorithm (http://fathmm.biocompute.org.uk/). And, it also has been associated with poor prognosis in acute myeloid leukemia,11 whereas other studies failed to establish this prognostic effect12 Based on the small number of patients (3 cases with PMF and 1 with MF post-PV) carrying this variation in our series and none of them evolved to acute leukemia during the follow-up, we could not assess the prognostic value of the IDH1 c.315 C>T variant in our MF population.…”