Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia.
Journal
Experimental hematology
ISSN: 1873-2399
Titre abrégé: Exp Hematol
Pays: Netherlands
ID NLM: 0402313
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
05
09
2019
revised:
10
10
2019
accepted:
14
10
2019
pubmed:
5
11
2019
medline:
19
2
2020
entrez:
4
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31678370
pii: S0301-472X(19)31072-0
doi: 10.1016/j.exphem.2019.10.001
pmc: PMC6910948
mid: NIHMS1542135
pii:
doi:
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
16-25.e3Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK056621
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA108671
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL053762
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134684
Pays : United States
Informations de copyright
Copyright © 2019 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
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