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A retinoid-resistant acute promyelocytic leukemia subclone expresses a
dominant negative PML-RAR alpha mutation
W Shao, L Benedetti, WW Lamph, C Nervi and WH Miller
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish
General Hospital and McGill University Department of Oncology, Montreal,
Quebec, Canada.
The unique t(15;17) of acute promyelocytic leukemia (APL) fuses the PML
gene with the retinoic acid receptor alpha (RAR alpha) gene. Although
retinoic acid (RA) inhibits cell growth and induces differentiation in
human APL cells, resistance to RA develops both in vitro and in patients.
We have developed RA-resistant subclones of the human APL cell line, NB4,
whose nuclear extracts display altered RA binding. In the RA-resistant
subclone, R4, we find an absence of ligand binding of PML-RAR alpha
associated with a point mutation changing a leucine to proline in the
ligand-binding domain of the fusion PML-RAR alpha protein. In contrast to
mutations in RAR alpha found in retinoid- resistant HL60 cells, in this NB4
subclone, the coexpressed RAR alpha remains wild-type. In vitro expression
of a cloned PML-RAR alpha with the observed mutation in R4 confirms that
this amino acid change causes the loss of ligand binding, but the mutant
PML-RAR alpha protein retains the ability to heterodimerize with RXR alpha
and thus to bind to retinoid response elements (RAREs). This leads to a
dominant negative block of transcription from RAREs that is dose-dependent
and not relieved by RA. An unrearranged RAR alpha engineered with this
mutation also lost ligand binding and inhibited transcription in a dominant
negative manner. We then found that the mutant PML-RAR alpha selectively
alters regulation of gene expression in the R4 cell line. R4 cells have
lost retinoid-regulation of RXR alpha and RAR beta and the RA-induced loss
of PML-RAR alpha protein seen in NB4 cells, but retain retinoid-induction
of CD18 and CD38. Thus, the R4 cell line provides data supporting the
presence of an RAR alpha-mediated pathway that is independent from gene
expression induced or repressed by PML- RAR alpha. The high level of
retinoid resistance in vitro and in vivo of cells from some relapsed APL
patients suggests similar molecular changes may occur clinically.
Volume 89,
Issue 12,
pp. 4282-4289,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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