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Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.



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Fang, Zijian 
Corbizi Fattori, Giuditta 
Boucher, Rebecca H 
Jackson, Aimee 


Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed 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% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.



Humans, Myeloproliferative Disorders, Janus Kinase 2, Hematopoietic Stem Cells, Signal Transduction, Neoplasms, Tamoxifen, Mutation, Calreticulin

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Nat Commun

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Springer Science and Business Media LLC
Italian Association for Cancer Research (AIRC) (Fellowship Rif. 20930)
MRC (MR/V005421/1)
Cancer Research UK (A27831)
Cancer Research UK (C61367/A26670)
NHS Blood and Transplant (NHSBT)
European Research Council (648765)
Wellcome Trust (203151/Z/16/Z)
MRC (MC_UU_00015/2)
Medical Research Council (MC_PC_17230)