Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia.

Megakaryocytes have been implicated in the micro-environmental abnormalities associated with fibrosis and hematopoietic failure in the bone marrow (BM) of primary myelofibrosis (PMF) patients, the Philadelphia-negative myeloproliferative neoplasm (MPN) associated with the poorest prognosis. To identify possible therapeutic targets for restoring the BM functions in PMF, we compared the expression profiling of PMF BM with that of BM from essential thrombocytopenia (ET), a fibrosis-free MPN also associated with BM megakaryocyte hyperplasia. The signature of PMF BM was also compared to published signatures associated with liver and lung fibrosis. Gene enrichment analysis identified distinctive differences between the expression profile of PMF and ET. Notch, K-Ras, IL-8 and apoptosis pathways were altered the most in PMF as compared to controls. By contrast, cholesterol homeostasis, unfolded protein response and hypoxia were the pathways found altered to the greatest degree in ET compared to control specimens. BM from PMF expressed a non-canonical TGF-β signature which included activation of ID1, JUN, GADD45b and of genes with binding motifs for the JUN transcriptional complex AP1. By contrast, the expression of ID1 and GADD45b was not altered and there was a modest signal for JUN activation in ET. The similarities among PMF, liver and lung fibrosis were modest and included activation of integrin-α9 and tropomyosin-α1 between PMF and liver fibrosis, and ectoderm-neural cortex protein1 and FRAS1-related extracellular matrix protein1 between PMF and lung fibrosis, but not TGF-β. These data identify TGF-β as a potential target for micro-environmental therapy in PMF.