Positive and negative regulation of granulopoiesis by endogenous RARα

Acute promyelocytic leukemia (APL) is always associated with chromosomal translocations that disrupt the retinoic acid receptor α (RARα) gene. Whether these translocations relate to a role for endogenous RARα in normal granulopoiesis remains uncertain because most studies addressing this question have used non-physiological overexpression systems. Granulocyte differentiation in cells derived from RARα-deficient (RARα−/−) mice was studied and evaluated in the context of agonist-bound and ligand-free RARα. Our results demonstrate that RARα is dispensable for granulopoiesis, as RARα−/− mice have a normal granulocyte population despite an impaired ability to respond to retinoids. However, although it is not absolutely required, RARα can bidirectionally modulate granulopoiesis. RARα stimulates differentiation in response to exogenous retinoic acid. Furthermore, endogenous retinoids control granulopoiesis in vivo, as either vitamin A–deficient mice or animals treated with an RAR antagonist accumulate more immature granulocytes in their bone marrow. Conversely, RARα acts to limit differentiation in the absence of ligand because granulocyte precursors from RARα−/− mice differentiate earlier in culture. Thus, the block in granulopoiesis exerted by RARα fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RARα.