Somatic and Germ-Line Molecular Characteristics Of Prefibrotic Myelofibrosis

Abstract Prefibrotic myelofibrosis (pre-MF) is a prodromic variant of primary myelofibrosis (PMF) characterized by prevalence of female sex, young age, high frequency of splanchnic vein thrombosis and indolent disease course (Barosi et al, PLoS One. 2012;7(4):e35631). Here we report the molecular characteristics at diagnosis of 177 consecutive pre-MF patients included in the institutional data-base of PMF patients at the Center for the Study of Myelofibrosis in Pavia from January 2001 through July 2013. As compared with patients with fibrotic type-MF (bone marrow (BM) fibrosis= 1 to 3), the frequency of JAK2V617F mutation in pre-MF patients (BM fibrosis=0) was higher (69.2% vs. 60.9%; P=0.02) but the JAK2V617F allele burden was lower (39% vs. 50.6%; P=<0.001). Patients with pre-MF displayed MPL, EZH2 or ASXL1 mutation at a frequency of 2.6%, 0% and 0% respectively, lower than in fibrotic type-MF (frequency: 7.6%, 4%, 17.4%, respectively). Both 45/1 haplotype of the JAK2 gene (rs12343867), and A3669G polymorphism of the glucocorticoid receptor (GR)- rs6198, known susceptibility alleles for PMF, were over-represented in pre-MF with respect to the normal control population (minor allele frequency, 43.3% vs. 24%, and 22.5% vs. 18.2%, respectively; P<0.001 and P= 0.04, respectively). However, the frequency of the variants were not significantly different in pre-MF with respect to fibrotic type-MF (minor allele frequency, 43.4% vs. 46.9%, and 22.5% vs. 27.1%). In pre-MF JAK2V617F mutated patients, a significant correlation between the burden of the V67F allele and the frequency of 46/1 haplotype (rs 12343867) was documented. By dividing JAK2V617F mutated patients in quartiles of allele burden, the frequency of the minor C allele increased progressively from 0.29% to 0.71% (P<0.001, X2 test for trend). No association was ascertained between the burden of the V617F allele and G allele of CR A3669G polymorphism. In conclusion, pre-MF patients segregated preferentially with JAK2V617F mutated genotype with low allele burden. Pre-MF patients were characterized by an almost complete absence of the acquired somatic mutations (EZH2 and ASXL1) that complement the JAK2V617F mutation in the fibrotic type-MF, and that are known to be associated to poor survival and propensity to blast transformation. Pre-MF patients were associated with susceptibility alleles 46/1 and GR A3669G, and the strength of association was not different from that of the fibrotic type-MF patients. Disclosures: No relevant conflicts of interest to declare.