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The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth
inhibition of human CD34+ erythroid progenitor cells
LS Rusten, I Dybedal, HK Blomhoff, R Blomhoff, EB Smeland and SE Jacobsen
Department of Immunology, Institute for Cancer Research, The Norweigian
Radium Hospital, Oslo.
Previous studies have shown that retinoic acid (RA), similar to tumor
necrosis factor-alpha (TNF-alpha), can act as a bifunctional regulator of
the growth of bone marrow progenitors, in that it can stimulate
granulocyte-macrophage colony-stimulating factor (GM-CSF)- or interleukin-3
(IL-3)-induced GM colony formation, but potently inhibit G-CSF-induced
growth. The present study, using highly enriched human CD34+ as well as
Lin- murine bone marrow progenitor cells, demonstrates a potent inhibitory
effect of 9-cis-RA on burst-forming unit-erythroid (BFU-E) colony formation
regardless of the cytokine stimulating growth. Specifically, 9-cis-RA
potently inhibited the growth of BFU-E response to erythropoietin (Epo)
(100%), stem cell factor (SCF) + Epo (92%), IL- 3 + Epo (97%), IL-4 + Epo
(88%), and IL-9 + Epo (100%). Erythroid colony growth was also inhibited
when CD34+ progenitors were seeded at one cell per well, suggesting a
direct action of RA. Using synthetic ligands to retinoic acid receptors
(RARs) and retinoid X receptors (RXRs) that selectively bind and activate
RAR-RXR or RXR-RXR dimers, respectively, we dissected the involvement of
the two retinoid response pathways in the regulation of normal myeloid and
erythroid progenitor cell growth. Transactivation studies showed that both
the RAR (Ro 13- 7410) and RXR (Ro 25-6603 and Ro 25-7386) ligands were
highly selective at 100 nmol/L. At this concentration, Ro 13-7410 potently
inhibited G- CSF-stimulated myeloid as well as SCF + Epo-induced erythroid
colony growth. At the same concentration, Ro 25-6603 and Ro 25-7386 had
little or no effect on G-CSF-induced colony formation, whereas they
inhibited 75% and 53%, respectively, of SCF + Epo-stimulated BFU-E colony
growth. Thus, the RAR-RXR response pathway can signal growth inhibition of
normal bone marrow myeloid and erythroid progenitor cells. In addition, we
demonstrate a unique involvement of the RXR-RXR pathway in mediating growth
inhibition of erythroid but not myeloid progenitor cells.
Volume 87,
Issue 5,
pp. 1728-1736,
03/01/1996
Copyright © 1996 by The American Society of Hematology
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