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In this study, we analysed known drugs in zebrafish embryos for their ability to selectively kill <jats:italic>tet2<\/jats:italic>\u2010mutant HSPCs in vivo. We found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill <jats:italic>tet2<\/jats:italic>\u2010mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murine <jats:italic>Tet2<\/jats:italic>\u2010deficient Lineage\u2010, Sca1+, Kit+ (LSK) cells, and also <jats:italic>TET2<\/jats:italic>\u2010inactivated human acute myeloid leukaemia (AML) cells. Selective killing of <jats:italic>TET2<\/jats:italic>\u2010mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased \u03b3H2AX expression. The finding that <jats:italic>TET2<\/jats:italic> loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of the selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of <jats:italic>TET2<\/jats:italic>\u2010mutant haematopoietic malignancies, and to suppress clonal expansion in age\u2010related <jats:italic>TET2<\/jats:italic>\u2010mutant clonal haematopoiesis.<\/jats:p>","DOI":"10.1111\/bjh.18667","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T01:04:05Z","timestamp":1675731845000},"page":"489-501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synthetic lethal targeting of <scp><i>TET2<\/i><\/scp>\u2010mutant haematopoietic stem and progenitor cells by <scp>XPO1<\/scp> inhibitors"],"prefix":"10.1111","volume":"201","author":[{"given":"Chang\u2010Bin","family":"Jing","sequence":"first","affiliation":[{"name":"Department of Pediatric Oncology Dana\u2010Farber Cancer Institute, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Prutsch","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Dana\u2010Farber Cancer Institute, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuning","family":"He","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Dana\u2010Farber Cancer Institute, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Dana\u2010Farber Cancer Institute, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosef","family":"Landesman","sequence":"additional","affiliation":[{"name":"Karyopharm Therapeutics  Newton Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7851-8617","authenticated-orcid":false,"given":"A. 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