The BCR/ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous but related group of clonal stem cell disorders characterised by the proliferation of one or more of the myeloid lineages in the bone marrow. These disorders, which include essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF), are characterised by an increased risk of thrombotic and haemorrhagic complications, fibrotic progression and transformation to acute leukaemia.
The genomic basis of MPN has been elucidated from analyses of cell lines, haemopoietic stem cells and/or blood leucocytes. The JAK2 V617F mutation is present in >97% of PV and up to 60% of ET and PMF patients and results in constitutive activation of the JAK-STAT signalling cascade. Recently somatic mutations in the endoplasmic reticulum chaperone CALR have been identified in the majority of patients with JAK2/MPL-unmutated ET and PMF. Mutations are also present in JAK2 exon 12 (2% PV), MPL (5-10% ET and PMF), and, less frequently in negative regulators of the JAK-STAT pathway (i.e. LNK, CBL and SOCS). Mutations targeting epigenetic regulator genes (including TET2, EZH2 and ASXL1) have also been implicated in the genetic pathology of MPN.
Megakaryocytes are the most pathological cells in MPN. Megakaryocytes differ from all other haemopoietic cells in that they undergo a unique maturation process whereby they increase their ploidy by endomitosis. This results in large polyploid cells with up to 128N nuclear material. In spite of the universal megakaryocytic hyperplasia and pleiomorphism in all MPN entities few studies have specifically addressed their cellular and molecular pathology. We are undertaking a systematic review of the biology of megakaryocytes in MPN. This is to determine whether additional mutations occur during the multiple rounds of megakaryocytic endoreduplication and whether these result in aberrant expression of their encoded protein products. Data will be presented of the cellular and molecular mapping of megakaryocytes in human bone marrow of MPN patients.