The molecular pathogenesis of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by the proliferation of cells of one or more of the myeloid lineages. The three major subgroups of MPN, namely PV, ET, and PMF, have been shown to exhibit the same gene mutations such as JAK2, MPL, and CALR. As JAK2 mutant mice developed three type of MPNs as PV, ET, or PMF, and CALR mutant mice developed ET, both JAK2 and CALR mutants played a driver role in MPN. The frequencies of hematopoietic stem cells (HSCs) in bone marrow (BM) increased in mice with JAK2 or CALR mutation compared to WT mice, however, HSCs with JAK2 mutation or CALR mutation exhibited a reduced growth advantage relative to wild-type (WT) HSCs in competitive transplantation assay, suggesting that JAK2 mutation or CALR mutation is insuffi cient for MPN onset. In addition to the above driver mutations, mutations in epigenetic regulators have been reported in MPN patients. Among them, TET2 mutation was observed in 10-20% of MPN patients, and frequently associated with JAK2 mutation. Cooperation between mutant JAK2 and mutant TET2 compensated for impaired HSC functioning by JAK2 mutation, and developed MPNs in the serial transplantation assay.