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Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: clonal evolution is a limiting factor
Authors:Christina Papadaki  Annika Dufour  Marlene Seibl  Stephanie Schneider  Stefan K. Bohlander  Evelyn Zellmeier  Gudrun Mellert  Wolfgang Hiddemann   Karsten Spiekermann
Affiliation:Laboratory for Leukaemia Diagnostics and Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany
Abstract:Nucleophosmin ( NPM1 ) mutations in exon 12 represent the most frequent molecular aberrations in adult patients with acute myeloid leukaemia (AML). Molecular detection of NPM1 mutation A could be a useful marker for routine monitoring of minimal residual disease (MRD). We established a calibrator-normalized relative quantification real-time polymerase chain reaction (PCR) assay for NPM1 mutation A . ABL1 was used as a reference housekeeping gene and the NPM1 mutation A-containing OCI/AML3 cell line as a calibrator. Relative quantification was performed by calculating the NPM1 mutation A /ABL1 ratio which was normalized to the NPM1 mutation A /ABL1 ratio of OCI/AML3 calibrator cDNA. The assay showed a sensitivity of 10−5. The clinical usefulness was evaluated by monitoring MRD in 51 AML patients with NPM1 mutation A. In 27 patients analysed at diagnosis and after induction treatment, NPM1 mutation A ratios showed a median log10 reduction of 2·48, which correlated with response to therapy. Among the 51 patients, 21 relapsed and two lost the mutation. We established a sensitive, specific and reproducible assay for routine quantification and monitoring of NPM1 mutation A levels. However, clonal evolution was observed in 9·5% limiting the usefulness of the NPM1 mutation A mutation as a molecular marker in these patients.
Keywords:NPM1 mutation    acute myeloid leukaemia    minimal residual disease    quantitative real-time RT-PCR
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