Quantitative Detection of DNMT3A R882H Mutation in Course of Treatment of Acute Myeloid Leukemia Patients

Autor: Claudia D. Baldus, Olga Blau, Bernd Doerken, Axel Nogai, Nikola Suckert, Rimma Berenstein, Kathrin Rieger, Igor Wolfgang Blau, Antonio Pezzutto
Rok vydání: 2015
Předmět:
Zdroj: Blood. 126:4970-4970
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v126.23.4970.4970
Popis: Introduction: DNMT3A mutation is one of the most common somatic mutations in acute myeloid leukemia (AML) patients with normal karyotype. The most frequent mutation is located at R882 codon in the methyltransferase domain. Because of prognostic significance and high stability during the disease evolution, DNMT3A mutations might represent highly informative biomarkers for prognosis and outcome of disease. Methods: Using allele-specific PCR with a Blocking reagent (ASB-PCR assay) for the quantitative detection of DNMT3A R882H mutation, we analyzed 350 follow-up samples from 28 AML patients in complete remission (CR) after induction and consolidation treatment and allogeneic stem cell transplantation (alloSCT). Seventeen patients included in the follow-up analysis harbored a NPM1 mutation. Using a well-established marker for the detection of minimal residual disease (MRD) allowed to estimate the stability of DNMT3A mutation in CR and complete molecular remission (molCR). In addition, we analyzed FLT3, IDH1, and IDH2 mutations in diagnostic and follow up samples and donor chimerism after alloSCT. Results: We found the persistence of DNMT3A R882H mutations in all patients in CR after standard therapy. On the contrary, after alloSCT, DNMT3A R882H mutation was not found in patients with CR and complete donor chimerism. In relapse of leukemia, an increasing of both NPM1 and DNMT3A mutated alleles were shown all cases. Conclusion: Persistence of DNMT3A mutation after standard chemotherapy could indicate the origin of mutation in the early pre-leukemic stem cells. The loss of correlation between NPM1 and DNMT3A in CR could be associated with leukemic clone evolution. It is impotant to note, that the removal of mutated leukemic stem cells after allo SCT indicates therapeutic options allo SCT for high risk AML patients. Increased of both DNMT3A and NPM1 mutated alleles in relapse indicates the presence of both mutations, at least partly, in the same leukemic clone. We conclude that quantitative detection of DNMT3A R882H mutations at different time points of AML disease could provide additional information about the role of mutations in development and progression of AML. Disclosures Blau: BMS: Honoraria; MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ Pharma: Honoraria; Shire: Honoraria; Janssen: Honoraria, Research Funding; Baxalta: Honoraria.
Databáze: OpenAIRE
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