IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.
By Guido Marcucci, K. Maharry, Yue-zhong Wu, Michael D. Radmacher, K. Mrózek, D. Margeson, Kelsi B. Holland, S. Whitman, H. Becker, S. Schwind and 10 more. Journal of Clinical Oncology, 2010
780 citations recorded by the source corpus.
PURPOSE To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
Subfields: Cancer Research, Hematology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/07b5b0f684dd7ee870dcc6b5ea411ef7c5517541
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cancer Research
- M. V. Vander Heiden
- Craig B. Thompson
- Patrick S. Ward
- Chuan He
- Hao Wu
- V. Fantin
- Ralph J. Deberardinis
- C. V. Dang
In Hematology
In Pulmonary and Respiratory Medicine
Citations in the corpus
- Genomic Classification and Prognosis in Acute Myeloid Leukemia (2016, neutral): “AML with TP53 mutations, chromosomal aneuploidy, or both‡ 199 (13) Complex karyotype (68), −5/5q (47), −7/7q (44), TP53 (44), −17/17p (31), −12/12p (17), +8/8q (16)”
- Targeting cancer metabolism: a therapeutic window opens (2011, background): “Mutations in IDH define a clinically distinct subset of both glioma and leukaemia, which suggests that these mutations contribute to a unique biology within each tumour typ”
- Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “Recurrent somatic mutations of IDH1/2 are frequently found in glioma and AML patients (Parsons et al. 2008; Mardis et al. 2009; Yan et al. 2009; Gross et al. 2010; Marcucci et al. 2010; Ward et al. 2010).”
- Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. (2017, neutral): “Platelets, 310(9)/L 39 (1-372) 44 (1-507) 45 (1-644)”
- The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Follow-up candidate-gene sequencing efforts later found IDH2 mutations in glioma and in AML (55, 56).”
- R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, result): “, 2015), and a similar trend, although still debatable (Marcucci et al., 2010), was reported in AML patients (Chou et al.”
- Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation (2010, background): “%) and preleukemic clonal malignancies including myelodysplasia andmyeloproliferative neoplasms ( 5% of chronic phase and 20% of transformed cases) (Marcucci et al., 2010; Mardis et al., 2009; Paschka et al., 2010; Tefferi et al., 2010;Wagner et al., 2010;Ward et al., 2010).”
- DNMT3A Mutations in Acute Myeloid Leukemia (2010, neutral): “IDH2 13/217 (6) 1/37 (3) 6/25 (24) 7/62 (11) 0.”