Whole-genome sequencing of myeloproliferative neoplasms revealed dynamic clonal changes in the fibrotic or leukemic transformation and novel FOXP1 mutations in the fibrotic transformation

Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of hematopoietic stem cells, which can lead to secondary myelofibrosis or acute myeloid leukemia. We explored the changes in genomic alterations during MPN transformation using whole-genome sequencing of samples from both the chronic and fibrotic or leukemic phases of 20 patients. We identified FOXP1 mutations in 3 of 14 (21.4%) patients with secondary myelofibrosis. This novel mutation was identified in another 5 of the 35 patients (14.3%) in an independent cohort. All these 8 patients with FOXP1 mutations did not experience leukemic transformation after a median follow-up of 5.1 years. The acquisition of non-canonical MPL^Y591 mutations was detected in the fibrotic or leukemic phase. Clonal expansion, involving both known and unknown driver genes (in 18 and 2 patients, respectively), was observed in all patients. We determined the patterns of clonal evolution based on myeloid driver mutations in 18 patients: linear clonal evolution in 11 patients and branched clonal evolution in 7 patients. Our results suggested that MPN patients carrying FOXP1 mutations are unlikely to have leukemia transformation and emphasized that the acquisition of specific genetic mutations and dynamic changes in clonal architecture underlie the pathogenesis in patients undergoing MPN transformation.