Persistence of DNMT3A mutations at long‐term remission in adult patients with AML. (4th August 2014)

• Record Type: Journal Article
• Authors: Pløen, Gro G.; Nederby, Line; Guldberg, Per; Hansen, Maria; Ebbesen, Lene H.; Jensen, Uffe Birk; Hokland, Peter; Aggerholm, Anni
• Is Part Of: British journal of haematology. Volume 167:Number 4(2014:Nov.)
• Page Start: 478
• Page End: 486
• Publication Date: 2014-08-04
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13062
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh13062-abs-0001"> <title>Summary</title> <p>Mutations in <italic>DNMT3A</italic>, the gene encoding DNA methyltransferase 3 alpha, have been identified as molecular drivers in acute myeloid leukaemia (AML) with possible implications for minimal residual disease monitoring and prognosis. To further explore the utility of <italic>DNMT3A</italic> mutations as biomarkers for AML, we developed assays for sensitive detection of recurrent mutations affecting residue R882. Analysis of DNA from 298 diagnostic AML samples revealed <italic>DNMT3A</italic> mutations in 45 cases (15%), which coincided with mutations in <italic>NPM1</italic>, <italic> FLT3</italic> and <italic>IDH1</italic>. <italic>DNMT3A</italic> mutations were stable in 12 of 13 patients presenting with relapse or secondary myelodysplastic syndrome, but were also present in remission samples from 14 patients (at allele frequencies of <1–50%) up to 8 years after initial AML diagnosis, despite the loss of all other molecular AML markers. The mutant <italic>DNMT3A</italic> allele burden was not related to the clinical course of disease. Cell sorting demonstrated the presence of <italic>DNMT3A</italic> mutations in leukaemic blasts, but also at lower allele frequencies in T and B‐cells from the same patients. Our data are consistent with the recent finding of preleukaemic stem cells in AML, which are resistant to chemotherapy. The persistence of <italic>DNMT3A</italic> mutations during remission may have important implications for the management of AML.</p> </abstract>