DH element reading frame selection is influenced by an Ig heavy chain transgene, but not by bcl-2

Mouse B cell precursors containing Ig D_HJ_H junctions in one particular reading frame are selectively lost during B cell development. In this register, arbitrarily referred to as reading frame 2, D_HJ_H junctions give rise to an open reading frame starting upstream of the D_H element and including the D_HJ_H-peptide fused to the constant region of IgM. Expression of this protein, called Dμ, has been strongly implicated in the loss of B cell precursors containing reading frame 2 D_HJ_H junctions. In an attempt to elucidate the means of Dμ counterselection, we have examined the reading frame distribution of D_HJ_H junctions in peripheral B cells from mice transgenic for either the human bcl-2 oncogene or for a functionally rearranged Ig μ heavy chain. In bcl-2 transgenic mice, reading frame 2 accounted for <5% of the D_HJ_H junctions in peripheral B cells, a value not significantly different from controls. Reading frames 1 and 3 were equally represented among the remaining junctions. By contrast, the reading frame distribution of endogenous D_HJ_H junctions in splenic B cells from Ig μ heavy chain transgenic mice showed no evidence of bias against Dμ encoding D_HJ_H junctions. Reading frames 2 and 3 accounted for 27% and 30% of the sequenced D_HJ_H junctions, respectively, and the remaining 43% were reading frame 1. Thus although the presence of BCL-2 cannot prevent the selective loss of reading frame 2 D_HJ_H B cells, a functional μ heavy chain can. These results suggest that Dμ-expressing B cell precursors may be selectively lost because of the premature and inappropriate cessation of heavy chain gene rearrangement rather than because of the induction of an apoptotic process which can be blocked by BCL-2.