Publication Date:
2016-12-02
Description:
The majority of patients diagnosed with Philadelphia negative (Ph-) myeloproliferative neoplasms (MPNs) harbor somatic, gain-of-function mutations in JAK2, CALR or MPL. All of these mutations are associated with constitutive JAK/STAT signaling which confers a proliferative advantage to MPN cells and leads to malignant myeloid expansion at the expense of normal hematopoiesis. The bone marrow (BM) microenvironment in MPNs, particularly myelofibrosis (MF), is characterized by high concentrations of inflammatory cytokines, and we have previously shown that MF cells generate tumor necrosis factor alpha (TNF) in a JAK2-dependent manner. Elevated TNF promotes the survival of JAK2V617F mutant cells over their JAK2WT counterparts, creating a feedback loop in which the mutant cells enhance the inflammatory environment that supports their survival and expansion (Fleischman et al. Blood. 2011 Dec 8;118(24):6392-8). To determine which hematopoietic lineages contribute to increased levels of TNF in MPN, we measured intracellular TNF expression in immunophenotypically defined white blood or BM cells from MF patients and normal controls. TNF expression was relatively low in unstimulated cells. However, lipopolysaccharide (LPS) treatment induced a 16-fold greater increase of TNF expression in hematopoietic stem cells (HSCs) from MF patients relative to normal controls (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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