title: Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations.
abstract: Nucleophosmin (NPM1) mutations in exon 12 are the most common genetic alternation in cytogenetically normal AML (CN-AML). Although mutation types A, B, and D represent the majority of cases, rare mutation variants of the NPM1 gene in individual patients do occur. In this study, we have evaluated a novel, DNA-based real-time quantitative polymerase chain reaction (RQ-PCR) for the detection of three of the most commonly occurring mutations and for six rare patient-specific mutation types, which represent 28% of all of the NPM1 mutations in our group of 25 CN-AML patients. Furthermore, the prognostic relevance of NPM1-based monitoring of minimal residual disease (MRD) in peripheral blood (PB), bone marrow (BM), and in specific cell subsets (CD34(+), CD34(-), CD34(dim)) of BM were evaluated. In 80% of the evaluable patients, a molecular relapse preceded a hematological relapse. Moreover, in this subset of patients, the molecular relapse occurred at a median of 97 days before the hematological relapse. Our compartment analysis showed a strong correlation between BM and PB (r = 0.907, P < 0.001) as well as a high copy number of mutated NPM1 in CD34(+) BM cells. In conclusion, we have demonstrated applicability of our presented RQ-PCR method for a large percentage of mutated NPM1 patients with CN-AML as well as the usefulness for long-term follow-up monitoring of MRD and the prediction of hematological relapse.
authors.affiliation: Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Dvorakova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Racil
authors.forename: Ivana
authors.initials: I
authors.lastname: Jeziskova
authors.forename: Ivo
authors.initials: I
authors.lastname: Palasek
authors.forename: Marketa
authors.initials: M
authors.lastname: Protivankova
authors.forename: Martina
authors.initials: M
authors.lastname: Lengerova
authors.forename: Filip
authors.initials: F
authors.lastname: Razga
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001773:Blood Cells; D001854:Bone Marrow Cells; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018365:Neoplasm, Residual / Q000175:diagnosis* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D012008:Recurrence
chemical_list: D018952:Antigens, CD34; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin