Fang, Zijian, Corbizi Fattori, Giuditta, McKerrell, Thomas, Boucher, Rebecca H., Jackson, Aimee, Fletcher, Rachel S., Forte, Dorian, Martin, Jose-Ezequiel, Fox, Sonia, Roberts, James, Glover, Rachel, Harris, Erica, Bridges, Hannah R., Grassi, Luigi, Rodriguez-Meira, Alba, Mead, Adam J., Knapper, Steven ![]() ![]() |
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Abstract
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.
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Schools > Medicine |
Additional Information: | License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access |
Publisher: | Nature Research |
ISSN: | 2041-1723 |
Date of First Compliant Deposit: | 27 November 2023 |
Date of Acceptance: | 2 November 2023 |
Last Modified: | 27 Nov 2023 14:45 |
URI: | https://orca.cardiff.ac.uk/id/eprint/164404 |
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