Aberrant Expression of Ikaros Induces T-Cell Leukemia/Lymphoma in Mice without Wild-Type Allelic Loss.

The Ikaros gene consisting of seven exons codes a family member of zinc finger transcription factors essential for establishment of immune systems. A number of isoform proteins are produced by alternative splicing. The activity of Ikaros is strictly regulated by total expression level or mutual dimerization with full-length and dominant-negative isoforms. Findings from Ikaros mutant mice revealed its characteristics as tumor suppressor in addition to functions of hemato-lymphoid development and differentiation. Mutant mice homozygous for lack of dimerization domains evolve T-cell leukemia and lymphoma. Heterozygous mutation of DNA binding domains can also lead to clonal expansion of T-cells through loss of heterozygosity. In both of murine models reported earlier, leukemias arise from the absence of full-length active isoforms. On the other hand, analyses for human diseases conducted by our group elucidated high incidence of over-expression of dominant-negative isoform in adult precursor B-lymphoblastic leukemia. Thus the mechanisms by which Ikaros contribute to leukemogenesis are critical issues to be clarified especially in human. Here, we demonstrate that over-expression of dominant-negative isoform causes leukemia and lymphoma without wild-type allelic loss by murine BMT assay. Retroviral gene transfer of dominant-negative isoform, Ik6, to murine hematopoietic cells developed lethal lympho-proliferative disorders in 3–6 months of latency with complete penetrantion. The diseases involved a variety of organs such as thymus, lymphnode, spleen, liver and bone marrow. Clonality of the infiltrating cells was confirmed by Southern blotting. The leukemic cells showed T-cell phenotype (B220-CD3e+CD4+CD8a+TCRb+Gr1-Mac1-) and express simultaneously full-length Ikaros proteins and transduced dominant-negative isoform. These data suggest that leukemogenesis mediated by decreased activity of Ikaros does not require deletion of full-length isoforms, and disproportional expression of Ikaros directed to dominant-negative isoform is enough to accumulate and immortalize lymphoid blasts in vivo. Silencing dominant-negative Ikaros proteins should be considered as a good candidate of molecular targeted therapy, and quantification of Ikaros isoforms might be useful for monitoring the minimal residual disease.