Whole-Exome sequencing of Triple-Negative Primary Myelofibrosis cases

Philadelphia-negative myeloproliferative neoplasms (MPN) are a group of clonal disorders characterized by the mutually exclusive presence of acquired somatic mutations in Janus kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia virus oncogene (MPL) genes. MPN include three principal entities: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). Virtually all the PV cases are caused by somatic mutations occurring in exon 14 or 12 of JAK2. Identical JAK2 mutations account for 60% of ET and PMF cases. Somatic mutations in exon 9 of CALR are instead responsible for 20% of ET and 25% of PMF cases and exon 10 MPL mutations for 3% and 7% of ET and PMF, respectively. However, a subset of ET (12-17%) and PMF (5-8%) disorders shows no evidence of these somatic variants; hence these patients are referred to as Triple-Negative MPN (TN-MPN). To investigate the nature of the TN-PMF, we selected a curated cohort of 12 PMF cases showing no evidence of JAK2, MPL or CALR somatic variants at high or low variant allele frequency and we characterized them by using high-coverage whole-exome sequencing.