Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia

Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the I karos gene as a tumor suppressor gene in mice. This prompted us to investig ate whether mutations in Ikaros play a role in human hematological malignan cies. Reverse transcription-PCR was used to determine the relative expressi on Levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lin es and human bone marrow samples from patients with hematological malignanc ies. Among the cell lines examined, only BV-173, which was derived from a c hronic myelogenous Leukemia (CML) patient in lymphoid blast crisis, overexp ressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastica lly reducing mRNA expression (4 of 17) or by overexpressing the dominant-ne gative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hemato logical malignancies. In some cases, overexpression of the dominant-negativ e Ik-6 protein was confirmed by Western blot analysis, and Southern blot an alysis indicated that decreases in Ikaros activity correlated with a mutati on in the Ikaros Locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast cr isis in CML and provide further evidence that mutations that alter Ikaros e xpression may contribute to human hematological malignancies.