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

Genta Ishikawa, Naoto Fujiwara, Hadassa Hirschfield, Lilian Varricchio, Yujin Hoshida, Giovanni Barosi, Vittorio Rosti, Maria Padilla, Maria Mazzarini, Scott L. Friedman, Ronald Hoffman, Anna Rita Migliaccio

Research output: Contribution to journalArticle

Abstract

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 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 with published signatures associated with liver and lung fibrosis. Gene set enrichment analysis (GSEA) identified distinctive differences between the expression profiles of PMF and ET. Notch, K-Ras, IL-8, and apoptosis pathways were altered the most in PMF as compared with controls. By contrast, cholesterol homeostasis, unfolded protein response, and hypoxia were the pathways found altered to the greatest degree in ET compared with control specimens. BM from PMF expressed a noncanonical transforming growth factor β (TGF-β) signature, which included activation of ID1, JUN, GADD45b, and 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 fibrosis, and lung fibrosis were modest and included activation of integrin-α9 and tropomyosin-α1 between PMF and liver fibrosis, and of ectoderm–neural cortex protein 1 and FRAS1-related extracellular matrix protein 1 between PMF and lung fibrosis, but not TGF-β. These data identify TGF-β as a potential target for micro-environmental therapy in PMF.

Original languageEnglish
Pages (from-to)16-25.e3
JournalExperimental Hematology
Volume79
DOIs
Publication statusPublished - Nov 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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    Ishikawa, G., Fujiwara, N., Hirschfield, H., Varricchio, L., Hoshida, Y., Barosi, G., Rosti, V., Padilla, M., Mazzarini, M., Friedman, S. L., Hoffman, R., & Migliaccio, A. R. (2019). Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia. Experimental Hematology, 79, 16-25.e3. https://doi.org/10.1016/j.exphem.2019.10.001