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Retinoic acid is required for and potentiates differentiation of acute
promyelocytic leukemia cells by nonretinoid agents
A Chen, JD Licht, Y Wu, N Hellinger, W Scher and S Waxman
Rochelle Belfer Chemotherapy Foundation Laboratory, Mount Sinai School of
Medicine, New York, NY.
Patients with acute promyelocytic leukemia (APL) associated with the
t(15;17) translocation and fusion of the promyelocytic leukemia (PML) and
retinoic acid receptor-alpha (RAR-alpha) genes achieve complete remission
but not cure with all-trans retinoic acid (RA), NB4, a cell line derived
from a patient with t(15;17) APL that undergoes granulocytic
differentiation when treated with pharmacologic doses of RA, was used as a
model for differentiation therapy of APL. We found that NB4 cells are
resistant to differentiation by nonretinoid inducers such as hexamethylene
bisacetamide (HMBA), butyrates, vitamin D3, or hypoxanthine, all of which
can induce differentiation in the commonly used HL60 leukemia cell line.
Preexposure of NB4 cells to low concentrations of RA for a period as short
as 30 minutes abolished resistance to nonretinoids and potentiated
differentiation. Sequential RA and HMBA treatment yielded maximal
differentiation by 3 days of drug exposure, whereas the effect of RA alone
peaked after 6 days and yielded a smaller percentage of differentiated
cells. RA also reversed NB4 cell resistance to butyrates and allowed for
synergistic differentiation by these agents. Pretreatment with HMBA before
exposure to RA failed to stimulate differentiation. Sequential RA/HMBA
treatment also markedly increased the extent of differentiation of primary
cultures of bone marrow and peripheral blood mononuclear cells from three
APL patients. In one case RA/HMBA treatment overcame resistance to RA in
vitro. Together, these results suggest that intermittent low doses of RA
followed by either HMBA or butyrates may be a useful combination in the
treatment of APL. This clinical strategy may help prevent or overcome RA
resistance in APL.
Volume 84,
Issue 7,
pp. 2122-2129,
10/01/1994
Copyright © 1994 by The American Society of Hematology
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