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While most patients achieve complete remission, approximately 40% of them still relapse. Early identification and elimination of leukaemia clones with relapse potential could improve prognosis for t(8;21) AML patients. Here, through single\u2010cell RNA sequencing, we characterized the intra\u2010tumoral heterogeneity of t(8;21) AML and identified haematopoietic stem cell (HSC)\u2010like subset as the most quiescent and primitive subgroup among all leukaemia cell populations. Further investigations revealed <jats:italic>IKZF2<\/jats:italic> as the master regulator for HSC\u2010like subset. Notably, <jats:italic>IKZF2<\/jats:italic> was upregulated in t(8;21) AML compared with other AML subtypes and was specifically targeted by AML1\u2010ETO. Using primary samples and mouse models, we verified the high enrichment of <jats:italic>IKZF2<\/jats:italic> in primitive and quiescent leukaemic cells. Moreover, <jats:italic>IKZF2<\/jats:italic> knockout hindered the accumulation of aberrant stem cells driven by AML1\u2010ETO and promoted cellular differentiation both in\u00a0vitro and in\u00a0vivo. These facilitate a better understanding of the leukaemia cell heterogeneity in t(8;21) AML and unveil <jats:italic>IKZF2<\/jats:italic> as a potential target for improving current treatment strategies.<\/jats:p>","DOI":"10.1111\/bjh.70077","type":"journal-article","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T05:44:32Z","timestamp":1754718272000},"page":"1309-1322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Single\u2010cell transcriptome profiling reveals blast cell heterogeneity and identifies novel therapeutic target <scp>IKZF2<\/scp> in t(8;21) acute myeloid leukaemia"],"prefix":"10.1111","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1979-7713","authenticated-orcid":false,"given":"Yu","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell 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Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology &amp; Blood Diseases Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Tianjin China"},{"name":"Tianjin Institutes of Health Science  Tianjin China"},{"name":"Department of Hematology, Sichuan Academy of Medical Sciences &amp; Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology &amp; Blood Diseases Hospital Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Tianjin China"},{"name":"Tianjin Institutes of Health Science  Tianjin 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