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Somatic cells acquire stem cell-like properties during cancerous transformation; however, mechanisms through which committed cells develop stemness and malignancy remain largely unknown. Here we uncovered upregulated stem cell program in leukaemic lymphoblasts of patients with  IKZF1  alterations by analysing the archived gene-expression profiling datasets. We then used a frequent  IKZF1  deletion, IK6, as a model via transduction into human primitive haematopoietic cells, followed by xenotransplantation in mice. Immunophenotypically defined stem, pro-B, and immature/mature (IM/M)-B cells were collected from primary recipients for functional assay and transcriptome profiling. Successful reconstitution in secondary recipient mice revealed the stemness of IK6 +  pro-B and IM/M-B cells. Upregulated stemness and malignancy programs in IK6 +  cells confirmed IK6 effects. Interestingly, these programs corresponded to distinct canonical pathways. Remarkably, the pathway profile mapped in the modelled cells well mirrored that in patients’ leukaemic cells; therefore, our study provides a seminal insight into the cancerous reprogramming of somatic cells.

Leukaemic alterations of IKZF1 prime stemness and malignancy programs in human lymphocytes