Ras mediates effector pathways responsible for pre-B cell survival, which is essential for the developmental progression to the late pre-B cell stage

Ras is essential for the transition from early B cell precursors to the pro -B stage, and is considered to be involved in the signal cascade mediated b y pre-B cell antigen receptors. To examine the role of p21(ras) in the late stage of B cell differentiation, we established transgenic mice (TG) expre ssing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage c ells at high levels after the early B cell precursor stage. Expression of p 21(Asn-17) (Ha-ras) was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. inhibition of p21(ras) activity markedly reduced the life span of p re-B cells, due, at least in part, to downregulation of the expression of a n antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21(ras) activ ity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 (Ha-ras) TG reversed the reduction in the number of lat e pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangemen t and progressing to immature B cells. These results suggest that p21(ras) mediates effector pathways responsible for pre-B cell survival, which is es sential for progression to the late pre-B and immature B stages.