Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2

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THE putative oncogene bcl -2 is juxtaposed to the immunoglobulin heavy chain ( Igh ) locus 1-3 by the t(14;18) chromosomal translocation typical of human follicular B-cell lymphomas 4 . The bcl -2 gene product (refs 5,6) is not altered by the translocation, but its expression is deregulated 6–8 , presumably by the Igh enhancer Eµ. Constitutive bcl -2 expression seems to augment cell survival, as infection with a bcl-2 retrovirus enables certain growth factor-dependent mouse cell lines to maintain viability when deprived of factor 9,10 . Furthermore, high levels of the bcl -2 product can protect human B and T lymphoblasts under stress 11,12 and thereby confer a growth advantage 12–14 . Mice expressing a bcl -2 transgene controlled by the Igh enhancer accumulate small non-cycling B cells which survive unusually well in vitro 15–17 but do not show a propensity for spontaneous tumorigenesis 15,16 . In contrast, an analogous myc transgene, designed to mimic the myc–Igh translocation product typical of Burkitt's lymphoma and rodent plasmacytoma 18 , promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells 19-22 . Previous experiments have suggested that bcl -2 can cooperate with deregulated myc to improve in vitro growth of pre-B and B cells 9,11 . Here we describe a marked synergy between bcl -2 and myc in doubly transgenic mice. Eµ– bcl –2/ myc mice show hyperproliferation of pre-B and B cells and develop tumours much faster than Eµ– myc mice. Surprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.

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B-Lymphocytes Leukocytes Cell Line Chromosomes, Human, Pair 14 Chromosomes, Human, Pair 18 Animals Mice, Transgenic Humans Mice Lymphoma