Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival

Bcl-2, which can both reduce apoptosis and retard cell cycle entry, is thou ght to have important roles in hematopoiesis. To evaluate the impact of its ubiquitous overexpression within this system, we targeted expression of th e human bcl-2 gene in mice by using the promoter of the vav gene, which is active throughout this compartment but rarely outside it. the vav-bcl-2 tra nsgene was expressed in essentially all nucleated cells of hematopoietic ti ssues but not notably in nonhematopoietic tissues. Presumably because of en hanced cell survival, the mice displayed increases in myeloid cells as well as a marked elevation in B and T lymphocytes. The spleen was enlarged and the lymphoid follicles expanded. Although total thymic cellularity was norm al, T cell development was altered: cells at the very immature and most mat ure stages were increased, whereas those at the intermediate stage were dec reased. Unexpectedly, blood platelets were reduced by half, suggesting that their production from megakaryocytes is regulated by the Bcl-2 family. Col ony formation by myeloid progenitor cells in vitro remained cytokine depend ent, and the frequency of most progenitor and preprogenitor cells was norma l. Macrophage progenitors were less frequent and yielded smaller colonies, however, perhaps reflecting inhibitory effects of Bcl-2 on cell cycling in specific lineages. After irradiation or factor deprivation, Bcl-2 markedly enhanced clonogenic survival of all tested progenitor and preprogenitor cel ls. Thus, Bcl-2 has multiple effects on the hematopoietic system. These mic e should help to further clarify the role of apoptosis in the development a nd homeostasis of this compartment.