A patient with a 20-year lag phase between JAK2-V617F+ myeloproliferation and NPM1-mutated AML arguing against a common origin of disease Anne Stidsholt Roug 1 , Charlotte Guldborg Nyvold 1 , Caroline Juhl-Christensen 1 , Mariann Christensen 2 , Susanne Schnittger 3 , Peter Hokland 1 Departments of 1 Hematology and 2 Pathology, Aarhus University Hospital, Aarhus, Denmark; 3 Munich Leukemia Laboratory (MLL), Munich, Germany The development of acute myeloid leukemia (AML) is generally regarded as a multistep process involving different pathogenic mechanisms, which ultimately result in the leukemic phenotype. In addition, there is a grow- ing body of evidence of intraclonal heterogeneity within myeloid neoplasms (1). The chronic myeloproliferative neoplasms (MPNs) comprise a group of stem-cell disor- ders [polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)] with preponder- ance to develop AML (2). Thus, the rate of leukemic transformation varies from 2% to 5% for PV, 15% for ET to 15–30% for patients with PMF (2–4). An acquired JAK2-V617F mutation (JAK2+) is present in the vast majority of patients with PV but at AML transforma- tion, the mutation is usually lost, resulting in a JAK2 wild-type AML clone (5). Irrespective of the latter, the study of preleukemic MPNs should allow for detection of mutations involved in early-stage leukemogenesis. In this regard, the transformation of a JAK2+ MPN to AML can be hypothesized to arise either in independent hematopoietic stem cells (HSCs) or from additional mutations in the same HSC (3). To what extent the JAK2 mutation per se contributes to leukemogenesis is at present not clear, but a subtype of AML-harboring mutations of the nucleophosmin (NPM1) gene has recently provided interesting insights. Here, mutations at the exon-12 is the underlying genetic lesion of 30% of adult patients with AML (60% of nor- mal karyotype AML) (6). Pasqualucci et al. reported the emergence of NPM1-mutated AML in a 61-yr-old woman 6 yr after JAK2+ PMF. Despite extensive molecular characterization, the cell origin of these two aberrations could not be unequivocally established (7). In a retrospective study of 67 transformed MPNs, Schnittger et al. very recently reported six patients with MPN found to be NPM1-mutated with two patients emanating from a JAK2+ MPN (one ET and one PV). The single patient with PV in that series displayed a Abstract We have sought to unravel the molecular biology of a female patient who in 1985 at the age of 55 was diagnosed with a chronic myeloproliferative neoplasm (MPN) and in whom overt acute myeloid leukemia (AML) developed in 2005. To this end, DNA and RNA (extracted from either paraffin-embedded bone mar- row (BM) or from BM and ⁄ or peripheral blood stored in an RNA ⁄ DNA-preserving buffer) were analyzed by qPCR and by capillary gel electrophoresis of PCR products. We found the patient to be JAK2-V617F muta- tion positive throughout the course of disease, while a mutation of the nucleophosmin (NPM1) gene emerged at AML diagnosis and relapse. The 20-yr lag phase between the polycythemia vera and the AML adds indirect evidence to the growing realization that the leukemic transformation in patients with MPN occurs from in a JAK2 wild-type stem cell. Key words JAK2-V617F; myeloproliferative neoplasms; acute myeloid leukemia; NPM1 Correspondence Anne S. Roug, MD, Department of Hematology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark. Tel: +45 89497584; Fax: 89497598; e-mail: roug@ki.au.dk Accepted for publication 15 June 2011 doi:10.1111/j.1600-0609.2011.01669.x CASE REPORT European Journal of Haematology 87 (461–463) ª 2011 John Wiley & Sons A/S 461