Megakaryocytic proteomic signatures define myeloproliferative neoplasms

The classical Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders of the bone marrow with significant niche dysregulation driven in part by abnormal megakaryocytes. The three classical MPNs: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), display established megakaryocytic morphological differences which aid in their diagnostic classification. The paucity of megakaryocytes in the bone marrow aspirate has previously limited a proteomic analysis of megakaryocytes in clinical samples. We aimed to undertake an unbiased proteomic analysis of in situ megakaryocytes from the bone marrow of patients with PV, ET, and PMF. Using a novel, deep visual proteomics strategy, we dissected and analyzed megakaryocytes from 60 MPN patients and 20 controls (patients with limited stage non-Hodgkin lymphoma who had uninvolved bone marrow). We reveal that megakaryocyte proteomics from MPN patients are distinct to those from control patients, and further, that the megakaryocytes from the three MPNs have unique, disease-specific signatures. The disease-specific megakaryocyte proteome highlights novel pathways of disease.