Single-cell transcriptome profiling reveals blast cell heterogeneity and identifies novel therapeutic target IKZF2 in t(8;21) acute myeloid leukaemia.

The t(8;21)(q22;q22) translocation is one of the most recurrent cytogenetic aberrations in acute myeloid leukaemia (AML). 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-cell RNA sequencing, we characterized the intra-tumoral heterogeneity of t(8;21) AML and identified haematopoietic stem cell (HSC)-like subset as the most quiescent and primitive subgroup among all leukaemia cell populations. Further investigations revealed IKZF2 as the master regulator for HSC-like subset. Notably, IKZF2 was upregulated in t(8;21) AML compared with other AML subtypes and was specifically targeted by AML1-ETO. Using primary samples and mouse models, we verified the high enrichment of IKZF2 in primitive and quiescent leukaemic cells. Moreover, IKZF2 knockout hindered the accumulation of aberrant stem cells driven by AML1-ETO and promoted cellular differentiation both in vitro and in vivo. These facilitate a better understanding of the leukaemia cell heterogeneity in t(8;21) AML and unveil IKZF2 as a potential target for improving current treatment strategies.