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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1758-1767
Targeting of PML/RAR Is Lethal to Retinoic Acid-Resistant
Promyelocytic Leukemia Cells
Kathryn Nason-Burchenal,
Janet Allopenna,
Agnes Bègue,
Dominique Stéhelin,
Ethan Dmitrovsky, and
Patrick Martin
From the Laboratory of Molecular Medicine, Department of Medicine and
Molecular Pharmacology and Therapeutics Program, Memorial
Sloan-Kettering Cancer Center, New York, NY; and CNRS UMR319 and CNRS
EP560, Institut Pasteur de Lille, Lille, France.
Acute promyelocytic leukemia (APL) cells, containing the t(15;17)
rearrangement, express the fusion protein, PML/RAR . Clinically, patients respond to all-trans retinoic acid (ATRA) through
complete remissions associated with myeloid maturation of leukemic
cells. This clinical ATRA response of APL is linked to PML/RAR
expression. Unfortunately, these remissions are transient and relapsed
APL is often ATRA-resistant. The role PML/RAR plays in the growth and maturation of these APL cells with acquired ATRA resistance has not
been fully explored. This study uses an ATRA-resistant NB4 cell line
(NB4-R1) to investigate the contribution of PML/RAR expression to
ATRA resistance. Targeting of PML/RAR in NB4-R1 cells was undertaken
using two approaches: homologous recombination and hammerhead
ribozyme-mediated cleavage. Reducing PML/RAR protein in NB4-R1 cells
rendered these cells more sensitive to ATRA. These cells were
growth-inhibited in ATRA, apoptosis was induced, and there was no
apparent signaling of differentiation. Sequence analysis identified a
mutation in the ligand binding domain (LBD) of the RAR portion of
PML/RAR. Results show that these retinoid-resistant NB4 cells
require persistent PML/RAR expression for leukemic cell growth.
Taken together, these findings can account for why these cells do not
respond to ATRA and how reduction of PML/RAR abrogates the
antiapoptotic effect it confers to these leukemic cells.
© 1998 by The American Society of Hematology.
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