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Impaired Granulocytic Differentiation In Vitro in Hematopoietic
Cells Lacking Retinoic Acid Receptors  1 and 
Jean Labrecque,
Deborah Allan,
Pierre Chambon,
Norman N. Iscove,
David Lohnes, and
Trang Hoang
From the Clinical Research Institute of Montréal,
Montréal, Québec, Canada; the Departments of Pharmacology,
Molecular Biology, and Biochemistry, Université de
Montréal, Montréal, Québec, Canada; the Laboratoire
de Génétique Moléculaire des Eukaryotes du CNRS,
Strasbourg, France; and the Ontario Cancer Institute, Toronto, Ontario,
Canada.
Transcripts for the retinoic acid receptors (RARs)  1, 2,  1,
and 2 were found in the granulocytic lineage (Gr-1+
cells) through semiquantitative polymerase chain reaction (PCR) analysis. The screening of single cell cDNA libraries derived from
hematopoietic progenitors also showed the presence of RAR and, to a
lesser extent, RAR transcripts in committed granulocyte (colony-forming unit-granulocyte [CFU-G]) or granulocyte-macrophage (CFU-GM) colony-forming cells. The contribution of RAR1 and to
hematopoietic cell differentiation was therefore investigated in mice
bearing targeted disruption of either one or both of these loci.
Because RAR and RAR1 compound null mutants die shortly after
birth, bone marrow cells were collected from fetuses at 18.5 days
postcoitum (dpc) and evaluated for growth and differentiation in
culture in the presence of Steel factor (SF), interleukin-3 (IL-3), and
erythropoietin (Epo). The frequency of colony-forming cells from bone
marrow populations derived from RAR1/ double null mice was not
significantly different from that of RAR or RAR1 single nulls or
from wild-type controls. In addition, the distribution of erythroid,
granulocyte, and macrophage colonies was comparable between
hematopoietic cells from all groups, suggesting that lineage commitment
was not affected by the lack of RAR1 and/or RAR. Colony
cells were then harvested individually and evaluated by morphologic
criteria. While terminal granulocyte differentiation was evident in
wild-type cells and colonies from either single null mutant, colonies
derived from RAR1 // bone
marrow populations were blocked at the myelocyte and, to a lesser
extent, at the metamyelocyte stages, whereas erythroid and macrophage
differentiation was not affected. Together, these results indicate that
both RAR1 and are required for terminal maturation in the
granulocytic lineage in vitro, but appear to be dispensable for the
early stages of hematopoietic cell development. Our results raise the
possibility that in acute promyelocytic leukemia (APL), the different
RAR fusion proteins cause differentiation arrest at a stage when
further maturation requires not only RAR, but also RAR. Finally,
bone marrow cells appear to differentiate normally in vivo, suggesting
an effective compensation mechanism in the RAR1/ double null
mice.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 607-615
© 1998 by the American Society of Hematology.
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