Identification of Driver and Subclonal Mutations in Myelofibrosis and Acute Myeloid Leukemia Post Classic Myeloproliferative Neoplasms (MPN).

SHEPS K; MEYER C; GUTIERREZ L; ENRICO A; HELLER P; RODRÍGUEZ ZUBIETA M; DE BRASI C; LARRIPA I

Mar del Plata

Congreso; LXI Reunión Científica Anual de la SAIC; 2016

Sociedad Argentina de Investigación Clínica

Introduction: Classic MPNs include polycythemiavera (PV), essential thrombocythemia (ET) and primary myelofibrosis (MF).Evolution to secondary myelofibrosis is part of the natural history of thefirst two syndromes and, at any stage, acute myeloid leukemia (AML) can beacquired. MPNs arecharacterized by the presence of driver oncogenic mutations in JAK2, CALR and MPL genes, beingmutually exclusive. Also, secondary subclonal mutations have  been reported in ASXL1, IDH1 and IDH2 genes, among others, associated withdisease progression. Aims: Analyze the presence of driversand subclonal mutations in patients with MF and AML post MPNs and determine itsprognostic impact. Patientsand Methods: DNA of 35 patients with MF or AML post MPN were analyzed. JAK2 V617F mutation was studied by DARMsPCR. The Allele burden of this mutation was assessed by qPCR. Type 1 and 2 CALR mutations (exon 9) wereinvestigated by PCR and electrophoresis. MPL(exon 10) and ASXL1 (exon 13)mutations were analyzed by PCR and direct sequencing. The mutations IDH1/2 werescreened by CSGE. Results: Mutations JAK2 V617F, CALR and MPLwere detected in 24 (68.5%), 3 (8.5%) and 2 (5.7%) cases respectively, 4(11.4%) were triple negative and in 2 cases the studies remain incomplete. Themean of the allele burden of the JAK2 V617Fmutation was 62.7%, plitting the patients into 2 groups with high and low levels.The analysis of exon 13 of ASXL1 revealed4 indels (3 not previously reported) and 3 rare missense variants. Five ofthese patients had disease progression or AML evolution. No mutations in the IDH1/2 genes have been detected yet. Discussion: Distribution of driver mutationsdiffers from the literature, with a higher prevalence of JAK2 V617F at expense of CALR.The highestallele burden was detected in patients with secondary MF post PV. ASXL1 indel mutations allowedidentifying patients at increased risk, reinforcing the importance of thesestudies to choose the best risk-adapted therapy.