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PLoS One. 2019 May 9;14(5):e0216810. doi: 10.1371/journal.pone.0216810. eCollection 2019.

Gene expression profiling distinguishes prefibrotic from overtly fibrotic myeloproliferative neoplasms and identifies disease subsets with distinct inflammatory signatures.

Author information

1
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
2
Nanostring Technologies Inc., Seattle, Washington, United States of America.
3
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) share similar molecular characteristics in that they frequently harbor hotspot mutations in JAK2, CALR or MPL, leading to activated JAK/STAT signaling. However, these MPN have distinct symptoms, morphology, and natural histories, including different tendencies to progress to fibrosis. Although the role of inflammation in tissue fibrosis is well recognized, inflammatory gene expression in bone marrows involved by MPN has been understudied. We analyzed the expression of inflammatory genes by directly measuring RNA transcript abundance in bone marrow biopsies of 108 MPN patients. Unsupervised analyses identified gene expression patterns that distinguish prefibrotic (grade 1-2) MPN from overtly fibrotic (grade 2-3) MPN with high sensitivity and specificity in two independent cohorts. Furthermore, prefibrotic and overtly fibrotic MPN are separable into subsets with different activities in biological pathways linked to inflammation, including cytokines, chemokines, interferon response, and toll-like receptor signaling. In conclusion, this study demonstrates that MPN with overt fibrosis is associated with significant inflammatory gene upregulation in the bone marrow, revealing potential roles for multiple pro-inflammatory signaling networks in the development of myelofibrosis and suggesting potential therapeutic mechanisms to alleviate this process in the bone marrow microenvironment.

Conflict of interest statement

The study was supported by a Brigham and Women’s Hospital Faculty Career Development Award (O.P.) and by the Brigham Research Institute and the Center for Faculty Development and Diversity’s Office for Research Careers Microgrant Program (O.P.). Dr. Kit Fuhrman is an employee of Nanostring Technologies, Inc; no funding was received from Nanostring Technologies for this study. Dr. Fuhrman’s role was limited to help with data validation. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Nanostring Technologies did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Other authors (WJW, OP, MB, AG, JCA and RHP) do not have commercial affiliation with the Nanostring Technologies, along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.

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