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Dominant Negative Isoform of the Ikaros Gene in Patients with Adult B-Cell Acute Lymphoblastic Leukemia

Department of Medicine, University of Okayama [K. Na., F. I., H. D., K. Matsuo, K. F., N. S., H. N., K. T., K. S., K. Ik., K. Ni., M. Harad.], Okayama Rousai Hospital [T. Y.], National Okayama Hospital [S. F.], Okayama Municipal Hospital [K. Im.], and National Sanatorium Minami Okayama Hospital [M. T.], Okayama 700-8558, Japan; Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuyama 721-0975, Japan [A. M.]; Ehime Prefectural Central Hospital [M. Hara], Department of Medicine, University of Ehime [M. Y.], Ehime 791-0295, Japan; Kochi Municipal Central Hospital [I. T.], Department of Medicine, Kochi Medical School [H. T.], Kochi 783-8505, Japan; Kameda General Hospital, Kamogawa 296-0041, Japan [K. Matsue]; Department of Medicine, University of Kanazawa, Kanazawa 920-8641, Japan [S. N.]; Department of Medicine, University of Kyushu, Fukuoka 812-8582, Japan [Y. N.]; and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129 [N. A.]

Gene targeting studies in mice have shown that the transcription factor Ikaros plays an essential role in lymphoid development and as a tumor suppressor in T cells, whereas the related gene Aiolos functions as a tumor suppressor in B cells. We analyzed the expression levels of the Ikaros gene family, Ikaros and Aiolos, in human bone marrow samples from patients with adult acute lymphoblastic leukemia [ALL (n = 46; B-cell ALL = 41; T-cell ALL = 5)]. Overexpression of the dominant negative isoform of Ikaros gene Ik-6 was observed in 14 of 41 B-cell ALL patients by reverse transcription-PCR, and the results were confirmed by sequencing analysis and immunoblotting. None of the other dominant negative isoforms of the Ikaros gene were detected by reverse transcription-PCR analysis. Southern blotting analysis with PstI digestion revealed that those patients with the dominant negative isoform Ik-6 might have small mutations in the Ikaros locus. We did not detect any overexpression of dominant negative isoforms of Aiolos in adult ALL patients. These results suggest that Ikaros plays a key role in human B-cell malignancies through the dominant negative isoform Ik-6.

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