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Mutations in the E-Domain of RAR Portion of the PML/RAR
Chimeric Gene May Confer Clinical Resistance to All-trans
Retinoic Acid in Acute Promyelocytic Leukemia
Masue Imaizumi,
Hoshiro Suzuki,
Miyako Yoshinari,
Atsushi Sato,
Toshiaki Saito,
Akira Sugawara,
Shigeru Tsuchiya,
Yoshiro Hatae,
Takeo Fujimoto,
Akira Kakizuka,
Tasuke Konno, and
Kazuie Iinuma
From the Departments of Pediatrics and Second Internal Medicine,
Tohoku University School of Medicine, Sendai, Japan; the Department of
Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku
University, Sendai, Japan; the Department of Pediatrics, National
Sapporo Hospital, Sapporo, Japan; the Department of Pediatrics, Aichi
Medical University, Aichi, Japan; and The 4th Department, Osaka
Bioscience Institute, Osaka, Japan.
The binding of all-trans retinoic acid (ATRA) to the
ligand-binding region in the E-domain of retinoic acid receptor-
(RAR) modifies the transcriptional activity of RAR protein. ATRA
probably induces differentiation of acute promyelocytic leukemia (APL) cells by binding to the E-domain of the RAR portion
(RAR/E-domain) of PML/RAR chimeric protein. Therefore, molecular
alteration in the RAR/E-domain of the chimeric gene is one mechanism
by which patients with APL may acquire resistance to ATRA therapy. In
this study using reverse transcription-polymerase chain reaction and
single-strand conformation polymorphism, DNA segments amplified from
the RAR/E-domain in fresh APL cells of 23 APL patients (8 males and
15 females from 4 to 76 years of age) were screened for mutations. Of
those patients, 3 patients (1 with de novo and 2 with relapse) had
clinical resistance to ATRA therapy. We found mutations in the
RAR/E-domain of PML/RAR chimeric gene exclusively in the 2 patients who exhibited ATRA-resistance at relapse, whereas the
mutations were not detected at their initial onset. Interestingly, these patients received a prolonged or intermittent administration of
ATRA before relapse with ATRA-resistance. The mutations lead to the
change of amino acid in the ligand-binding region of RAR/E-domain, Arg272Gln, or Met297Leu according to the amino acid sequence of RAR,
respectively. Further study demonstrated that the in vitro ligand-dependent transcriptional activity of the mutant PML/RAR protein was significantly decreased as compared with that of wild-type PML/RAR. These findings suggest that mutations in the
RAR/E-domain of the PML/RAR chimeric gene may confer clinical
resistance to ATRA therapy in patients with APL.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 374-382
© 1998 by the American Society of Hematology.
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