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Clinical Cancer Research Vol. 5, 2112-2120, August 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Expression of Dominant-Negative Ikaros Isoforms in T-Cell Acute Lymphoblastic Leukemia1

Lei Sun, Mya-Lisa Crotty, Martha Sensel, Harland Sather, Christopher Navara, James Nachman, Peter G. Steinherz, Paul S. Gaynon, Nita Seibel, Chen Mao, Alexei Vassilev, Gregory H. Reaman and Fatih M. Uckun2

Parker Hughes Cancer Center and Children’s Cancer Group ALL Biology Reference Laboratory, Hughes Institute, St. Paul, Minnesota 55113 [L. S., M-L. C., C. N., A. V., C. M., F. M. U.]; Group Operations Center, Children’s Cancer Group, Arcadia, California 91066 [H. S., M. S.]; Department of Pediatrics, University of Chicago, Chicago, Illinois 60601 [J. N.]; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [P. G. S.]; Department of Hematology-Oncology, Children’s Hospital Los Angeles, Los Angeles, California 90027 [P. S. G.]; and Children’s National Medical Center and the George Washington University, Washington, D.C. 20010 [N. S., G. H. R.]

Ikaros, a zinc finger-containing DNA-binding protein, is required for normal lymphocyte development. Germ-line mutant mice that express only non-DNA binding dominant-negative "leukemogenic" Ikaros isoforms lacking critical NH2-terminal zinc fingers develop an aggressive form of T-cell leukemia. We studied Ikaros gene expression in leukemic cells from 18 children with T-cell acute lymphoblastic leukemia (T-ALL). In each of the 18 T-ALL cases as well as JK-E6–1 and MOLT-3 cell lines, we found high-level expression of dominant-negative isoforms of Ikaros with abnormal subcellular compartmentalization patterns. Nuclear extracts from these cells failed to bind to the IKAROS-specific binding sequence in DNA. PCR cloning and sequencing confirmed that JK-E6–1 and MOLT-3 cell lines as well as leukemic cells from 9 of 10 patients with T-ALL expressed dominant-negative Ikaros isoforms Ik-4, Ik-7, and Ik-8 that lack critical NH2-terminal zinc fingers. In 6 of 10 patients, we detected a specific mutation leading to an in-frame deletion of 10 amino acids ({Delta} KSSMPQKFLG) upstream to the transcription activation domain and adjacent to the COOH-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. Thus, children with T-ALL express high levels of dysfunctional dominant-negative Ikaros isoforms.




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Copyright © 1999 by the American Association for Cancer Research.