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

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 TNFR2 as a key mediator of TNF-induced clonal expansion.

SMAC mimetics as potential cancer therapeutics in myeloid malignancies

“…XIAP and cIAPs mutually regulate expression by promoting the other's ubiquitination and proteasome degradation (Harlin et al, 2001). Corroborating with these findings are the promising early clinical activity of SMAC mimetic LCL-161 in MF (Pemmaraju et al, 2018) and pre-clinical data demonstrating TNF-induced apoptotic activity of birinapant (a bivalent IAP inhibitor) in MF cell lines at concentrations that selectively block cIAP, but not XIAP (Heaton et al, 2018). Elevated cIAP and downregulation of the pro-apoptotic MAPK8 through the aberrantly activated TNF-TNFR2 autocrine loop promotes NF-kB activation, which favours survival and promotes further inflammatory cytokine production (Hoesel & Schmid, 2013;Kleppe et al, 2018).…”

“…IAPs are preferentially upregulated in malignancy and confer drug resistance, and their overexpression is correlated, in several studies, with chemo‐resistance, tumour progression, and inferior survival outcomes (Tamm et al , ; Krajewska et al , ; Schimmer et al , ). Expression of IAPs is dysregulated in not only solid tumours but also a variety of haematological myeloid malignancies, such as acute myeloid leukaemia (AML) (Pluta et al , ), myelodysplastic syndrome (MDS) (Yamamoto et al , ), and myelofibrosis (MF) (Heaton et al , ).…”

“…Activated caspase-9 then initiates the caspase cascade culminating in apoptosis. of haematological myeloid malignancies, such as acute myeloid leukaemia (AML) (Pluta et al, 2015), myelodysplastic syndrome (MDS) (Yamamoto et al, 2004), and myelofibrosis (MF) (Heaton et al, 2018).…”

“…IAPs are implicated in several haematological malignancies, including multiple myeloma (MM)(Chauhan et al, 2007), AML(Carter et al, 2003a;Cassier et al, 2017), CML(Beider et al, 2014), MF(Heaton et al, 2018), chronic lymphocytic leukaemia(Kater et al, 2005;Balakrishnan et al, 2016), Hodgkin lymphoma(Kashkar et al, 2006) and aggressive non-Hodgkin lymphoma subtypes, such as diffuse large B cell lymphoma(Runckel et al, 2016) (Cillessen et al, 2008) among others. Several pre-clinical models have demonstrated…”

The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations

“…CD14 1 monocytes were isolated from the blood of untreated CMML patients (n 5 12; median age 72 years; range, 57-87), age-matched healthy controls (old controls, n 5 12; median age, 68 years; range, [62][63][64][65][66][67][68][69][70][71][72][73][74] and young healthy controls (young controls, n 5 16; median age, 29 years; range, and subjected to RNA sequencing. In addition, we performed DNA methylation profiling for the CMML patients and old controls.…”