Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment‐related pathways
TL;DR
It is highlighted that selinexor plus ruxolitinib affects both MF haematopoietic cell–intrinsic and microenvironment‐related pathways, providing a novel disease‐modifying strategy with the potential to improve clinical outcomes in patients with MF.
Abstract
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, marrow fibrosis, cytopenias and inflammation. Janus kinase 2 (JAK2) inhibitors, such as ruxolitinib, reduce splenomegaly and alleviate symptoms but have limited disease‐modifying activity, and resistance frequently develops. Selinexor, an oral selective exportin (XPO1) inhibitor, restores nuclear retention of tumour suppressors and inhibitors of inflammatory signalling. Dual XPO1/JAK2 inhibition targets complementary downstream pathways, enhancing suppression of MF progenitor cell fitness. We evaluated selinexor plus ruxolitinib in MF models, including JAK2V617F or calreticulin (CALR) exon 9‐mutant MPN cell lines and samples from patients with MF. The combination showed greater anti‐proliferative activity than JAK2 inhibition alone and suppressed colony formation from MF Cluster of Differentiation 34 (CD34)+ cells. Selinexor remained active in a ruxolitinib‐resistant MPN cell line, inducing G1 arrest and apoptosis. Multi‐omic analyses demonstrated increased nuclear retention of p53 and disruption of Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling, complementing and extending ruxolitinib‐targeted pathways. The combination suppressed NF‐κB transcriptional activity and reduced Tumor Necrosis Factor alpha (TNFα), Interleukin‐6 (IL‐6) and Monocyte Chemoattractant Protein‐1 (MCP‐1) secretion from MF patient peripheral blood mononuclear cells. These findings highlight that selinexor plus ruxolitinib affects both MF haematopoietic cell–intrinsic and microenvironment‐related pathways, providing a novel disease‐modifying strategy with the potential to improve clinical outcomes in patients with MF.