Accession Number:

AD1105409

Title:

Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

Descriptive Note:

Technical Report,15 Sep 2016,14 Sep 2019

Corporate Author:

University of California, Irvine Irvine United States

Personal Author(s):

• Fleischman,Angela

Report Date:

2020-01-01

Pagination or Media Count:

17.0

Abstract:

Patients with myeloproliferative neoplasms MPN have high levels of inflammatory cytokines some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone2. We report here that monocytes from MPN patients have defective negative regulation of Toll-Like Receptor TLR signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis alpha TNF- following TLR activation. Specifically, MPN patient monocytes are insensitive to the anti-inflammatory cytokine IL-10 that negatively regulates TLR induced TNF- production. This inability to respond to IL-10 is a not a direct consequence of JAK2V617F, the phenotype of persistent TNF- production is a feature of JAK2V617F and wild-type monocytes alike from JAK2V617F-positive patients. Moreover, persistent TNF- production was also discovered in the unaffected identical twin of an MPN patient suggesting that it could be an intrinsic feature of those predisposed to acquire MPN. This work implicates sustained TLR signaling as not only a contributor to the chronic inflammatory state of MPN patients but also as a potential predisposition to acquire MPN.

Descriptors:

• cytokines
• neoplasms
• inflammation
• hematologic diseases
• cell physiological processes
• monocytes
• therapy
• myeloid cells

Subject Categories:

• Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE