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Alternative pre-mRNA splicing is emerging as a major control point in both the initiation and progression of tumourigenesis. Overexpression of the dominant negative Ikaros splice isoform, Ik6, is found in many human cancers particularly leukaemias. Ik6 has been demonstrated to have a role in cell survival in both myeloid- and lymphoid cytokine-dependent cell lines. To investigate the oncogenic potential of Ik6, we retrovirally transduced murine haematopoietic progenitor cells with Ik6 and have analysed the effects on proliferation and differentiation of these precursors using myeloid and lymphoid in vitro colony formation assays. We found that Ik6 can immortalize haematopoietic progenitor cells in myeloid conditions. Using an in vivo transplantation assay, we found that Ik6 favours reconstitution by haematopoietic precursors. These findings suggest that Ik6 may play an important role in the generation of the leukaemic phenotype. © 2008 Wiley-Liss, Inc.