TRANSFORMING FUNCTION OF THE HOX11 TCL3 HOMEOBOX GENE/

The HOX11/TCL3 homeobox gene was identified at the breakpoint region i n pediatric T-cell acute lymphoblastic leukemia harboring 10q24 chromo somal translocations. We previously reported that primary murine bone marrow cells transduced ex vivo with a recombinant HOX11-containing re trovirus, MSCV-HOX11, gave rise to cell lines at high frequency having characteristics of early myeloid cells. Cell lines were also establis hed from the bone marrow and spleen of transplant recipients sacrifice d 5 months after engraftment with MSCV-HOX11-transduced bone marrow ce lls. These latter lines, which exhibited a more differentiated myelomo nocytic phenotype, harbored proviruses encoding a smaller HOX11 protei n. None of the mice that received HOX11-expressing bone marrow cells o r myeloid cell lines developed leukemia during 6-month observation per iods. Here, we report that two bone marrow transplant recipients event ually developed T-cell acute lymphoblastic leukemia-like malignancies at 7 and 12 months posttransplant, indicating that progression to a fu lly malignant state required additional mutations. One tumor synthesiz ed full-length HOX11 whereas the other expressed the smaller version o f the protein. The smaller HOX11 protein suffered a carboxyl-terminal truncation. We subsequently constructed MSCV-based retroviral vectors expressing deleted forms of HOX11 and identified an aminoterminal regi on that was dispensible for generation of myeloid cell lines having a similar phenotype as those induced by full-length HOX11. We thus concl ude that regions near the amino and carboxyl termini of HOX11 are not essential for transforming function, nor do they appear to determine t he lineage or stage of differentiation of the target cell for transfor mation.