TY - JOUR
T1 - Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion
AU - Heaton, William L.
AU - Senina, Anna V.
AU - Pomicter, Anthony D.
AU - Salama, Mohamed E.
AU - Clair, Phillip M.
AU - Yan, Dongqing
AU - Bell, Russell N.
AU - Gililland, Jeremy M.
AU - Prchal, Josef T.
AU - O’Hare, Thomas
AU - Deininger, Michael W.
N1 - Funding Information:
Conflict of interest MWD is on the advisory board and is a consultant for Incyte, Novartis, and Pfizer, and serves on the advisory board for Ariad, Blueprint, and Galena BioPharma. His laboratory receives research funding from Novartis and Pfizer.
Funding Information:
Acknowledgements This work was supported by a Leukemia & Lymphoma Society (LLS) Translational Research Program Award (6086-12) (MWD). We thank James Marvin, director of the Flow Cytometry Core Facility, at the University of Utah for his assistance with experimental design. We also thank Kim Reynolds and Mariko Sato for their technical assistance on the project.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Tumor necrosis factor alpha (TNF) is increased in myelofibrosis (MF) and promotes survival of malignant over normal cells. The mechanisms altering TNF responsiveness in MF cells are unknown. We show that the proportion of marrow (BM) cells expressing TNF is increased in MF compared to controls, with the largest differential in primitive cells. Blockade of TNF receptor 2 (TNFR2), but not TNFR1, selectively inhibited colony formation by MF CD34 + and mouse JAK2 V617F progenitor cells. Microarray of mouse MPN revealed reduced expression of X-linked inhibitor of apoptosis (Xiap) and mitogen-activated protein kinase 8 (Mapk8) in JAK2 V617F relative to JAK2 WT cells, which were normalized by TNFR2 but not TNFR1 blockade. XIAP and MAPK8 were also reduced in MF CD34 + cells compared to normal BM, and their ectopic expression induced apoptosis. Unlike XIAP, expression of cellular IAP (cIAP) protein was increased in MF CD34 + cells. Consistent with cIAP’s role in NF-κB activation, TNF-induced NF-κB activity was higher in MF vs. normal BM CD34 + cells. This suggests that JAK2 V617F reprograms TNF response toward survival by downregulating XIAP and MAPK8 through TNFR2. Our results reveal an unexpected pro-apoptotic role for XIAP in MF and identify TNFR2 as a key mediator of TNF-induced clonal expansion.
AB - Tumor necrosis factor alpha (TNF) is increased in myelofibrosis (MF) and promotes survival of malignant over normal cells. The mechanisms altering TNF responsiveness in MF cells are unknown. We show that the proportion of marrow (BM) cells expressing TNF is increased in MF compared to controls, with the largest differential in primitive cells. Blockade of TNF receptor 2 (TNFR2), but not TNFR1, selectively inhibited colony formation by MF CD34 + and mouse JAK2 V617F progenitor cells. Microarray of mouse MPN revealed reduced expression of X-linked inhibitor of apoptosis (Xiap) and mitogen-activated protein kinase 8 (Mapk8) in JAK2 V617F relative to JAK2 WT cells, which were normalized by TNFR2 but not TNFR1 blockade. XIAP and MAPK8 were also reduced in MF CD34 + cells compared to normal BM, and their ectopic expression induced apoptosis. Unlike XIAP, expression of cellular IAP (cIAP) protein was increased in MF CD34 + cells. Consistent with cIAP’s role in NF-κB activation, TNF-induced NF-κB activity was higher in MF vs. normal BM CD34 + cells. This suggests that JAK2 V617F reprograms TNF response toward survival by downregulating XIAP and MAPK8 through TNFR2. Our results reveal an unexpected pro-apoptotic role for XIAP in MF and identify TNFR2 as a key mediator of TNF-induced clonal expansion.
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U2 - 10.1038/s41375-018-0131-z
DO - 10.1038/s41375-018-0131-z
M3 - Article
C2 - 29749399
AN - SCOPUS:85046789004
SN - 0887-6924
VL - 32
SP - 2399
EP - 2411
JO - Leukemia
JF - Leukemia
IS - 11
ER -