Abstract
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.
References
May 25, 1992·Neuroscience Letters·T TominagaT Yoshimoto
Nov 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·N Takahashi, T R Breitman
May 26, 1991·The New England Journal of Medicine·R P WarrellA Jakubowski
Jul 17, 1995·Journal of Immunological Methods·I VermesC Reutelingsperger
Mar 1, 1993·Immunology Today·J SavillC Haslett
Jul 1, 1995·Leukemia & Lymphoma·M Cornic, C Chomienne
Jan 10, 1997·Experimental Cell Research·M Taimi, T R Breitman
Apr 7, 1997·Biochemical and Biophysical Research Communications·H UmemiyaK Shudo
May 1, 1997·Leukemia & Lymphoma·M KizakiY Ikeda
Nov 5, 1998·The New England Journal of Medicine·S L SoignetR P Warrell
Dec 22, 1999·The EMBO Journal·G BenoitM Lanotte
Jan 6, 2000·The Tohoku Journal of Experimental Medicine·M YoshinariK Iinuma
Feb 16, 2000·Leukemia·E DuprezM Lanotte
Feb 22, 2001·The Journal of Experimental Medicine·E M RegoP P Pandolfi
Feb 7, 2002·Blood·Da-Cheng ZhouRobert E Gallagher
Sep 20, 2002·Blood·Sylvie CôtéWilson H Miller