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Antisense RNA Inhibition of Phosphoprotein p18 Expression Abrogates the Transformed Phenotype of Leukemic Cells¹

Departments of Pediatrics and Hematology, M. D. Anderson Cancer Center, Houston, Texas 77030 [S. J., M. B., H. K.], and Department of Medicine and Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029 [X. L., G. F. A.]

Phosphoprotein p18 was identified originally on the basis of its very high level of expression in leukemic cells of different lineages. Changes in the level of p18 accumulation and phosphorylation associated with induction of differentiation of leukemic cells suggested a potential role for this phosphoprotein in cellular proliferation and differentiation and possibly in malignant transformation. Recent studies have demonstrated that p18 plays an important role in cell cycle progression by serving as a substrate for p34^cdc2 kinase. These studies showed that inhibition of p18 expression in leukemic cells results in growth retardation and accumulation of cells in G₂-M. In this study, we explore the potential role of p18 in cellular transformation by investigating the effects of inhibition of p18 expression on the malignant phenotype of K562 erythroleukemia cells. These studies show that antisense inhibition of p18 expression in leukemic cells results in growth arrest at a lower saturation density, loss of serum independence, and loss of anchorage-independent growth in vitro. In addition, inhibition of p18 expression results in a marked inhibition of tumorigenicity of leukemic cells in vivo in the severe combined immune deficiency mouse model. These studies demonstrate that the high level of p18 expression in leukemic cells is necessary for the maintenance of the transformed phenotype and suggest p18 as a potential target for antileukemic interventions.

¹ This work was supported by NIH PHS Grant HL-42919 (G. F. A.) and NIH General Clinical Research Center Grant M01-RR00071 (Mount Sinai School of Medicine).

² To whom requests for reprints should be addressed, at Division of Hematology, Box 1079, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-5293; Fax: (212) 369-8375.

Received 9/11/95. Accepted 1/15/96.

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