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Positive and negative regulation of granulopoiesis by endogenous RARalpha
P Kastner1, H J Lawrence, C Waltzinger
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. scpk@igbmc.u-strasbg.fr
Blood
|February 27, 2001
Summary
Retinoic acid receptor alpha (RARalpha) is not essential for granulopoiesis. However, RARalpha influences this process by stimulating differentiation with retinoic acid and limiting it without the ligand, potentially explaining Acute promyelocytic leukemia.
Area of Science:
- Hematology
- Molecular Biology
- Cellular Differentiation
Background:
- Acute promyelocytic leukemia (APL) involves chromosomal translocations affecting the retinoic acid receptor alpha (RARalpha) gene.
- The role of endogenous RARalpha in normal granulopoiesis is unclear due to reliance on overexpression systems.
Purpose of the Study:
- To investigate the role of endogenous RARalpha in granulopoiesis using RARalpha-deficient mice.
- To evaluate RARalpha's function in both ligand-bound and ligand-free states.
Main Methods:
- Analysis of granulocyte populations in RARalpha-deficient (RARalpha(-/-)) mice.
- Assessment of granulocyte differentiation in vitro and in vivo.
- Studies involving vitamin A-deficient mice and RAR antagonist treatment.
Main Results:
- RARalpha(-/-) mice exhibit normal granulocyte populations, indicating RARalpha is dispensable for granulopoiesis.
- RARalpha stimulates granulocyte differentiation in response to exogenous retinoic acid.
- Endogenous retinoids regulate granulopoiesis; deficiency or antagonism leads to immature granulocyte accumulation.
- In the absence of ligand, RARalpha limits differentiation, as RARalpha(-/-) precursors differentiate prematurely.
Conclusions:
- RARalpha is dispensable but plays a modulatory role in granulopoiesis.
- The mechanism of APL's granulopoiesis block may involve an amplified function of unliganded RARalpha.
- Endogenous retinoids are crucial regulators of normal granulopoiesis in vivo.