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 alpha (RAR alpha) gene. Whether these translocations relate to a role for endogenous RAR alpha. in normal granulopoiesis re mains uncertain because most studies addressing this question have used nonphysiological overexpression systems. Granulocyte differentiation in cells derived from RAR alpha -deficient (RAR alpha (-/-)) mice was studied and evaluated in the context of agonist-bound and ligand-free RAR alpha. Our results demonstrate that RAR alpha is dispensable for granulopoiesis, as RAR alpha (-/-) mice have a normal granulocyte population de spite an impaired ability to respond to retinoids. However, although it is not absolutely required, RAR alpha can bidirectionally modulate granulopoiesis. RAR alpha 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, RAR alpha acts to limit differentiation in the absence of ligand because granulocyte precursors from RAR alpha (-/-) mice differentiate earlier in culture. Thus, the block in granulopoiesis exerted by RARa fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RAR alpha. (Blood, 2001;97: 1314-1320) (C) 2001 by The American Society of Hematology.