Investigating the anti-leukaemic effect of tamoxifen in the myeloproliferative neoplasms
type: CreativeWork
description: Myeloproliferative neoplasms (MPNs) commonly result from the acquisition of somatic mutations affecting the Janus kinase 2 (JAK2) (such as JAK2V617F) or the multi-functional protein CALR (such as CALRIns5 and CALRDel52), causing the constitutive activation of signal transducer and activator of transcription (STAT) proteins. The selective oestrogen receptor modulator (SERM) tamoxifen (broadly used in ER+ breast cancer) was effective on eradiating JAK2V617F+ haematopoietic stem and progenitor cells (HSPCs) in preclinical mouse MPN models, which prompted a Phase-II clinical study (Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms, TAMARIN). In the TAMARIN study, the safety and activity of tamoxifen on reducing mutant allele burden was observed in a subset of MPN patients. This thesis investigated the mechanism of action of tamoxifen in human MPN. According to the transcriptomic analysis, HSPCs from patients meeting the primary or secondary endpoints (tamoxifen responders) were highly enriched with specific molecular pathways such as integrated stress response (ISR), proinflammatory signalling, mitochondrial activity and proteotoxic stress at baseline, implying a predictable transcriptomic signature for tamoxifen susceptivity. Moreover, immunoblotting showed that tamoxifen treatment induced a proapoptotic ISR in tamoxifen–sensitive JAK2V617F+ human cell lines, which manifested as increased translation of activating transcription factor 4 (ATF4) and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The knockdown of ATF4 and inhibition of eIF2α phosphorylation partially rescued tamoxifen-induced apoptosis. Despite the oestrogenic transcriptional regulation found in HSPCs from responders or JAK2V617F+ human cell lines, full-length oestrogen receptors α (ERα), the canonical transcriptional receptor of tamoxifen in mouse haematopoietic system, was not highly expressed in these cells, and the expression…
abstract: Myeloproliferative neoplasms (MPNs) commonly result from the acquisition of somatic mutations affecting the Janus kinase 2 (JAK2) (such as JAK2V617F) or the multi-functional protein CALR (such as CALRIns5 and CALRDel52), causing the constitutive activation of signal transducer and activator of transcription (STAT) proteins. The selective oestrogen receptor modulator (SERM) tamoxifen (broadly used in ER+ breast cancer) was effective on eradiating JAK2V617F+ haematopoietic stem and progenitor cells (HSPCs) in preclinical mouse MPN models, which prompted a Phase-II clinical study (Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms, TAMARIN). In the TAMARIN study, the safety and activity of tamoxifen on reducing mutant allele burden was observed in a subset of MPN patients. This thesis investigated the mechanism of action of tamoxifen in human MPN. According to the transcriptomic analysis, HSPCs from patients meeting the primary or secondary endpoints (tamoxifen responders) were highly enriched with specific molecular pathways such as integrated stress response (ISR), proinflammatory signalling, mitochondrial activity and proteotoxic stress at baseline, implying a predictable transcriptomic signature for tamoxifen susceptivity. Moreover, immunoblotting showed that tamoxifen treatment induced a proapoptotic ISR in tamoxifen–sensitive JAK2V617F+ human cell lines, which manifested as increased translation of activating transcription factor 4 (ATF4) and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The knockdown of ATF4 and inhibition of eIF2α phosphorylation partially rescued tamoxifen-induced apoptosis. Despite the oestrogenic transcriptional regulation found in HSPCs from responders or JAK2V617F+ human cell lines, full-length oestrogen receptors α (ERα), the canonical transcriptional receptor of tamoxifen in mouse haematopoietic system, was not highly expressed in these cells, and the expression…
author: Fang, Zijian
language: eng
keywords: haematopoietic stem and progenitor cells, JAK2V617F, myeloproliferative neoplasms, tamoxifen
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/80561be2-375a-429a-8bbd-9f64d5821c50/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-08-31
date modified: 2026-07-22T22:24:17Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.103276