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Transforming Function of the HOX11/TCL3 Homeobox Gene¹

Oncology Gene Therapy Program, The Toronto Hospital and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M1, Canada [R. G. H., A. Z. C. F., T. S. H.]; Department of Laboratory Medicine, Sunnybrook Health Science Centre, Toronto, Ontario M4N 3M5, Canada [M. D. R.]; and Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 [N. Z., M. L.]

The HOX11/TCL3 homeobox gene was identified at the breakpoint region in pediatric T-cell acute lymphoblastic leukemia harboring 10q24 chromosomal translocations. We previously reported that primary murine bone marrow cells transduced ex vivo with a recombinant HOX11-containing retrovirus, MSCV-HOX11, gave rise to cell lines at high frequency having characteristics of early myeloid cells. Cell lines were also established from the bone marrow and spleen of transplant recipients sacrificed 5 months after engraftment with MSCV-HOX11-transduced bone marrow cells. These latter lines, which exhibited a more differentiated myelomonocytic phenotype, harbored proviruses encoding a smaller HOX11 protein. None of the mice that received HOX11-expressing bone marrow cells or myeloid cell lines developed leukemia during 6-month observation periods. Here, we report that two bone marrow transplant recipients eventually developed T-cell acute lymphoblastic leukemia-like malignancies at 7 and 12 months posttransplant, indicating that progression to a fully malignant state required additional mutations. One tumor synthesized full-length HOX11 whereas the other expressed the smaller version of the protein. The smaller HOX11 protein suffered a carboxylterminal truncation. We subsequently constructed MSCV-based retroviral vectors expressing deleted forms of HOX11 and identified an aminoterminal region that was dispensible for generation of myeloid cell lines having a similar phenotype as those induced by full-length HOX11. We thus conclude that regions near the amino and carboxyl termini of HOX11 are not essential for transforming function, nor do they appear to determine the lineage or stage of differentiation of the target cell for transformation.

¹ This work was supported in part by grants from the National Cancer Institute of Canada (R. G. H.), the American Cancer Society (M. L.), and the Pete Lopiccola Memorial Foundation (M. L.).

² To whom requests for reprints should be addressed, at Oncology Research Laboratories, The Toronto Hospital, CRCS-424, 67 College Street, Toronto, Ontario M5G 2M1, Canada. Phone: (416) 340-3843; Fax: (416) 340-3453.

Received 9/ 4/96. Accepted 11/27/96.

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