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Departments of Medicine [H. N., F. I., N. S., N. F., K. N., M. H.] and Molecular Biology and Biochemistry [Y. N.], University of Okayama, Fujisaki Cell Center [A. H., J. M.], Okayama Municipal Hospital [J. T., K. I., T. T.], and Okayama National Hospital [S. F., T. S.], Okayama 700-8558, Japan; Ehime Prefectural Central Hospital, Ehime 790-0024, Japan [K. K., M. H.]; Kochi Municipal Central Hospital, Kochi 780-0821, Japan [H. T., S. Y., I. T.]; Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuyama, 721-0975 Japan [A. M.]; Hamanomachi Hospital [S. T.] and Department of Medicine [Y. T., H. G., Y. N.], University of Kyushu, Fukuoka 812-8582, Japan; Department of Medicine, University of Kanazawa, Kanazawa 920-8641, Japan [S. N.]; Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital [T. K., H. D.] and Department of Cancer Cytogenetics, Research Institute for Nuclear Medicine and Biology [N. K.], University of Hiroshima, Hiroshima 734-8553, Japan; Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129 [N. A.]
Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed 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 drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation 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 crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies.
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