Tamoxifen reduces mitochondrial respiration, oncogenic signaling and mutant allele burden in a myeloproliferative neoplasm subset

Current therapies for myeloproliferative neoplasms (MPN) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem and progenitor cells (HSPCs). TAMARIN is a Phase-II, multicenter, single-arm clinical trial assessing tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20%. The primary outcome (≥50% allele burden reduction at 24 weeks) was met by 3/38 patients; 5/38 additional patients showed ≥25% reductions. Tamoxifen was well tolerated. Baseline analysis of HSPC transcriptome segregated responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis showed high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which were downregulated by tamoxifen. In JAK2V617F+ cells, 4-hydroxytamoxifen inhibited mitochondrial complex-I, activating proapoptotic integrated stress response (ISR) and decreasing pathogenic JAK2 signaling. Therefore, tamoxifen inhibits mitochondrial respiration, modulates ISR and suppresses pathogenic JAK-STAT signaling in a subset of prospectively identifiable MPN patients.