Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARalpha chimeric gene.
Cellular response to all-trans retinoic acid (ATRA) of acute promyelocytic leukemia (APL) with patient-derived mutant PML-retinoic acid receptor-alpha (PML-RARalpha) was investigated using an APL cell line, UF-1, carrying Arg611Trp mutation in PML-RARalpha. Although the mutant protein showed a decreased ligand-dependent transcriptional activity and retained a dominant-negative effect on normal RARalpha, UF-1 cells underwent growth inhibition, maturation and apoptosis in response to ATRA at 1 microM, but not < or = 100 nM, after 4 days of treatment with ATRA. Moreover, in the presence of 1 microM ATRA, approximately 50% of UF-1 cells expressing annexin V, an early-apoptotic marker, was negative for CD11b and showed immature morphology. These findings suggest that UF-1 cells, despite expressing mutant PML-RARalpha protein, can be induced by ATRA to undergo differentiation and apoptosis through RA-inducible mechanism(s), in which a proportion of apoptosis may occur independent of terminal differentiation. This unique cell line may be useful for investigating the pathogenesis of ATRA resistance and the mechanism of ATRA-induced apoptosis in APL.
Sato
Atsushi
A
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Imaizumi
Masue
M
Hoshi
Yoshiyuki
Y
Rikiishi
Takeshi
T
Fujii
Kunihiro
K
Kizaki
Masahiro
M
Kagechika
Hiroyuki
H
Kakizuka
Akira
A
Hayashi
Yutaka
Y
Iinuma
Kazuie
K
D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014162:Transfection; D019076:Transgenes; D014212:Tretinoin / Q000494:pharmacology*
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin