Autocrine Tnf signaling favors malignant cells in myelofibrosis in a Tnfr2-dependent fashion

Leukemia
William L HeatonMichael W Deininger

Abstract

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 JAK2V617F progenitor cells. Microarray of mouse MPN revealed reduced expression of X-linked inhibitor of apoptosis (Xiap) and mitogen-activated protein kinase 8 (Mapk8) in JAK2V617F relative to JAK2WT 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 JAK2V617F 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...Continue Reading

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Citations

Mar 6, 2019·British Journal of Haematology·Prajwal BodduNaveen Pemmaraju
Mar 14, 2020·British Journal of Haematology·Donal P McLornan, Claire N Harrison
Apr 17, 2020·Leukemia & Lymphoma·Prithviraj Bose, Srdan Verstovsek
Apr 5, 2020·Expert Opinion on Investigational Drugs·Aniket Bankar, Vikas Gupta
Jan 10, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Jie LiChanggang Sun
Dec 31, 2019·Cell Biochemistry and Function·Miloš DiklićVladan P Čokić
Jan 25, 2019·Current Treatment Options in Oncology·Prithviraj BoseSrdan Verstovsek
Aug 3, 2019·Current Hematologic Malignancy Reports·Minas P EconomidesNaveen Pemmaraju
Jan 8, 2020·Experimental Hematology & Oncology·Brianna M CraverAngela G Fleischman
Mar 2, 2021·Hematology/oncology Clinics of North America·Naveen PemmarajuSrdan Verstovsek
Apr 30, 2021·The Journal of Clinical Investigation·Juliette LambertStéphane Prost
Jun 16, 2021·The Journal of Experimental Medicine·Francisco CaiadoMarkus G Manz
Jun 19, 2021·Frontiers in Immunology·Daniel Arthur Corpuz FisherStephen Tracy Oh

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Datasets Mentioned

BETA
GSE104792

Methods Mentioned

BETA
FACS
ELISA
biopsy
ubiquitination
biopsies

Software Mentioned

Affymetrix Expression Console
Affymetrix Command Console ( AGCC )
FlowJo

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