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Occurrence of resistance to retinoic acid in the acute promyelocytic
leukemia cell line NB4 is associated with altered expression of the pml/RAR
alpha protein
S Dermime, F Grignani, M Clerici, C Nervi, G Sozzi, GP Talamo, E Marchesi, F Formelli, G Parmiani and PG Pelicci
Division of Experimental Oncology D, B, and A, Istituto Nazionale Tumori,
Milan, Italy.
The mechanism(s) by which acute promyelocytic leukemia (APL) cells acquire
resistance to all-trans retinoic acid (ATRA) is poorly understood. We
describe here an APL cell line, named NB4.306, that shows resistance to the
anti-proliferative action of ATRA. This cell line is also operationally
resistant to most ATRA-induced phenotypic modifications (CD11b, CD11c,
CD13, and CD33). No significant differences in ATRA intracellular
accumulation, efflux, or metabolism were found between NB4.306 and the
parent NB4 cell line that could explain the observed resistance of the
NB4.306 line. The NB4.306 cell line was found to be positive for the t15;17
translocation and showed the usual pml/RAR alpha fusion bands in both
Southern and Northern blot assays, but expressed no detectable amount of
the usual pml/RAR alpha protein, as assayed by Western blot analysis using
an anti-RAR alpha antibody. These results were confirmed in 14 of 14 clones
obtained from the NB4.306 cell line, while 30 of 30 clones obtained from
the parental NB4 line expressed the usual 110-Kd fusion polypeptide. It is
concluded that the occurrence of resistance to ATRA in the NB4.306 cell
line is closely associated to the loss of expression of the intact pml/RAR
alpha protein.
Volume 82,
Issue 5,
pp. 1573-1577,
09/01/1993
Copyright © 1993 by The American Society of Hematology
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