Myelo fi brosis (MF) is caused by expansion of mutated hematopoietic stem and progenitor cells that results in bone marrow (BM) fi brosis, ineffective erythropoiesis, elevated in fl am-matory cytokines, and extramedullary hematopoiesis. Most MF patients experience constitutional symptoms that impair quality of life. Cytopenias, thromboembolism, and leukemic transformation cause morbidity and mortality [1]. Aberrant JAK/STAT pathway activation by mutations in JAK2 , CALR , or MPL is central to MF pathogenesis, and JAK inhibitors (JAKis) are the standard of care. Ruxolitinib, the fi rst JAKi approved for MF, effectively reduces spleen volume and symptoms in ~40% of patients, but many responses are only transient [2]. Myelosuppression frequently necessitates dose reduction, compromising symptom control. While JAK2 V617F variant allele frequency (VAF) and fi brosis are reduced in some patients, JAKis do not eliminate the malignant clone, leaving patients at risk of progression. The limited ef fi cacy of JAKis has stimulated research into targeting other pathways involved in MF pathogenesis [3]. Although activity was observed for several agents, to-date, JAKis have remained the only FDA-approved MF drugs. Allogeneic stem cell transplant (SCT), while potentially curative, is associated with high morbidity and mortality, and many patients are ineligible [4]. We have previously identi fi ed exportin-1 (XPO1)-mediated nuclear-cytoplasmic export (NCE) as a vulnerability in MF cells [5]. Selinexor, a fi rst-in-class XPO1 inhibitor approved for multiple myeloma
S. Tantravahi, Andrea A Ellero, Ami B. Patel et al.· Blood Cancer Journal· 1 citation
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.
T. Kashyap, Andrea A Ellero, C. Walker et al.· British Journal of Haematolo...· 0 citations
