Positive and negative regulation of granulopoiesis by endogenous RAR alpha

Acute promyelocytic leukemia (APL) is always associated with chromosomal tr anslocations that disrupt the retinoic acid receptor alpha (RAR alpha) gene . Whether these translocations relate to a role for endogenous RAR alpha. i n normal granulopoiesis re mains uncertain because most studies addressing this question have used nonphysiological overexpression systems. Granulocyt e differentiation in cells derived from RAR alpha -deficient (RAR alpha (-/ -)) mice was studied and evaluated in the context of agonist-bound and liga nd-free RAR alpha. Our results demonstrate that RAR alpha is dispensable fo r granulopoiesis, as RAR alpha (-/-) mice have a normal granulocyte populat ion de spite an impaired ability to respond to retinoids. However, although it is not absolutely required, RAR alpha can bidirectionally modulate gran ulopoiesis. RAR alpha stimulates differentiation in response to exogenous r etinoic acid. Furthermore, endogenous retinoids control granulopoiesis in v ivo, as either vitamin A-deficient mice or animals treated with an RAR anta gonist accumulate more immature granulocytes in their bone marrow. Converse ly, RAR alpha acts to limit differentiation in the absence of ligand becaus e 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 func tion of unliganded RAR alpha. (Blood, 2001;97: 1314-1320) (C) 2001 by The A merican Society of Hematology.