PU.1/Spi-B regulation of c-rel is essential for mature B cell survival

PU.1(+/-)Spi-B-/- mice exhibit reduced numbers of immature and mature B lym phocytes, which exhibit severe defects in response to BCR-mediated stimulat ion and poor survival. We found that expression of c-rel, a member of the R el/NF-kappaB family, is dramatically reduced in PU.1(+/-)Spi-B-/- splenic B cells. Analysis of the murine c-rel promoter identified three PU.1/Spi-B b inding sites critical for c-rel promoter activity. Furthermore, reintroduct ion of Rel protein restored wild-type B cell numbers to mice reconstituted with PU.1(+/-)Spi-B-/- bone marrow. These findings are the first to demonst rate that a member of the Rel/NF-kappaB family is directly regulated by Ets proteins and dissect the molecular basis for the function of two Ets facto rs, PU.1 and Spi-B, in promoting B lymphocyte survival.