Abstract
Primary blasts of a t(11;17)(q23;q21) acute promyelocytic leukaemia (APL) patient were analysed with respect to retinoic acid (RA) and arsenic trioxide (As2O3) sensitivity as well as PLZF/RARα status. Although RA induced partial monocytic differentiation ex vivo, but not in vivo, As203 failed to induce apoptosis in culture, contrasting with t(15;17) APL and arguing against the clinical use of As203 in t(11;17)(q23;q21) APL. Prior to cell culture, PLZF/RARα was found to exactly co-localize with PML onto PML nuclear bodies. However upon cell culture, it quickly shifted towards microspeckles, its localization found in transfection experiments. Arsenic trioxide, known to induce aggregation of PML nuclear bodies, left the microspeckled PLZF/RARα localization completely unaffected. RA treatment led to PLZF/RARα degradation. However, this complete PLZF/RARα degradation was not accompanied by differentiation or apoptosis, which could suggest a contribution of the reciprocal RARα/PLZF fusion product in leukaemogenesis or the existence of irreversible changes induced by the chimera.
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References
Borrow J, Goddart A, Sheer D and Solomon E . 1990 Science 249: 1577–1580.
Campbell IG, Nicolai HM, Foulkes WD, Senger G, Stamp GW, Allan G, Boyer C, Jones K, Bast RC, Solomon E, Trowsdale J and Black DM . 1994 Hum. Mol. Genet. 3: 589–594.
Chelbi-Alix MK, Pelicano L, Quignon F, Koken MHM, Venturini L, Stadler M, Pavlovic J, Degos L and de Thé H . 1995 Leukemia 9: 2027–2033.
Chen G-Q, Shi X-G, Tang W, Xiong S-M, Zhu J, Cai X, Han Z-G, Ni J-H, Shi G-Y, Jia P-M, Liu M-M, He K-L, Niu C, Ma J, Zhang P, Zhang T-D, Paul P, Naoe T, Kitamura K, Miller W, Waxman S, Wang Z-Y, de Thé H, Chen S-J and Chen Z . 1997a Blood 89: 3345–3353.
Chen G-Q, Zhu J, Shi X-G, Ni J-H, Zhong H-J, Si G-Y, Jin X-L and Al E . 1996 Blood 88: 1052–1061.
Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y and Evans RM . 1997b Cell 90: 569–580.
Chen Z, Brand N, Chen A, Chen S, Tong J, Wang Z, Waxman S and Zelent A . 1993 EMBO J. 12: 1161–1167.
Daniel M-T, Koken M, Romagné O, Barbey S, Bazarbachi A, Stadler M, Guillemin M, Degos L, Chomienne C and de Thé H . 1993 Blood 82: 1858–1867.
de Thé H, Chomienne C, Lanotte M, Degos L and Dejean A . 1990 Nature 347: 558–561.
de Thé H, Lavau C, Marchio A, Chomienne C, Degos L and Dejean A . 1991 Cell 66: 675–684.
Degos L . 1993 Leukaemia 7: 766–770.
Dhordain P, Albagli O, Lin R, Ansieau S, Quief S, Leutz A, Kerckaert JP, Evans R and Leprince D . 1997 Proc. Natl. Acad. Sci. USA 94: 10762–10767.
Dong S, Zhu J, Reid A, Strutt P, Guidez F, Zhong HJ, Wang ZY, Licht J, Waxman S, Chomienne C, Chen Z, Zelent A and Chen SJ . 1996 Proc. Natl. Acad. Sci. USA 93: 3624–3629.
Dyck JA, Maul GG, Miller WH, Chen JD, Kakizuka A and Evans RM . 1994 Cell 76: 333–343.
Grignani F, de Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S and Pelicci PG . 1998 Nature 391: 815–818.
Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S and Zelent A . 1998 Blood 91: 2634–2642.
He LZ, Tribioli C, Peruzzi D, Ruthard M, Catforetti G and Pandolfi PP . 1997 Blood 90: 320a.
Hong SH, David G, Wong CW, Dejean A and Privalsky ML . 1997 Proc. Natl. Acad. Sci. USA 94: 9028–9033.
Huang M, Ye Y, Chen R, Chai J, Lu J, Zhoa L, Gu L and Wang Z . 1988 Blood 72: 567–572.
Kakizuka A, Miller Jr, W, Umesono K, Warrell Jr, R, Frankel SR, Murty VV, Dmitrovsky E and Evans RM . 1991 Cell 66: 663–674.
Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub M-P, Durand B, Lanotte M, Berger R and Chambon P . 1992 EMBO J. 11: 629–642.
Koken MHM, Linares-Cruz G, Quignon F, Viron A, Chelbi-Alix MK, Sobczak-Thépot J, Juhlin L, Degos L, Calvo F and de Thé H . 1995 Oncogene 10: 1315–1324.
Koken MHM, Puvion-Dutilleul F, Guillemin MC, Viron A, Linares-Cruz G, Stuurman N, de Jong L, Szostecki C, Calvo F, Chomienne C, Degos L, Puvion E and de Thé H . 1994 EMBO J. 13: 1073–1083.
Koken MHM, Reid A, Quignon F, Chelbi-Alix MK, Davies JM, Kabarowski JHS, Zhu J, Dong S, Chen S-J, Chen Z, Tan CC, Licht J, Waxman S, de Thé H and Zelent A . 1997 Proc. Natl. Acad. Sci. USA 94: 10255–10260.
Li J-Y, English MA, Ball HJ, Yeyati PL, Waxman S and Licht JD . 1997 J. Biol. Chem. 272: 22447–22455.
Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, Michaux JL, Wu Y, DeBlasio A, Miller Jr, WH, Zelenetz AD, Willman CL, Chen Z, Chen S-J, Zelent A, Macintyre E, Veil A, Cortes J, Kantarjian H and Waxman S . 1995 Blood 85: 1083–1094.
Lin RJ, Nagy L, Inoue S, Shao WL, Miller WH and Evans RM . 1998 Nature 391: 811–814.
Mu ZM, Chin KV, Liu JH, Lozano G and Chang KS . 1994 Mol. Cell. Biol. 14: 6858–6867.
Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL and Evans RM . 1997 Cell 89: 373–380.
Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, LoCoco F, Grignani F and Pelicci PG . 1991 Oncogene 6: 1285–1292.
Quignon F, Chen Z and de Thé H . 1997 Biochim. Biophys. Acta 1333: M53–M61.
Raelson JV, Nervi C, Rosenauer A, Benedetti L, Monczak Y, Pearson M, Pelicci PG and Miller WH . 1996 Blood 88: 2826–2832.
Redner RL, Rush EA, Faas S, Rudert WA and Corey SJ . 1996 Blood 87: 882–886.
Sitterlin D, Tiollais P and Transy C . 1997 Oncogene 14: 1067–1074.
Stadler M, Chelbi-Alix MK, Koken MHM, Venturini L, Lee C, Saïb A, Quignon F, Pelicano L, Guillemin M-C, Schindler C and de Thé H . 1995 Oncogene 11: 2565–2573.
Weis K, Rambaud S, Lavau C, Jansen J, Carvalho T, Carmo-Fonseca M, Lamond A and Dejean A . 1994 Cell 76: 345–356.
Wells RA, Catzavelos C and Kamel-Reid S . 1997 Nat. Genet. 17: 109–113.
Yeyati PL, Shanovich R, Waxman S, Zelent A and Licht JD . 1997 Blood 90: 245a.
Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, Ohno R and Naoe T . 1996 Cancer Res. 56: 2945–2948.
Zhu J, Koken MHM, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, Chen Z and de Thé H . 1997 Proc. Natl. Acad. Sci. USA 94: 3978–3983.
Acknowledgements
We thank the LPH for their help with photography, and Michel Schmid and Christel Doliger for their excellent confocal microscopy analysis. Drs P Chambon and B Allegretto are thanked for the kind gift of antibodies. All members of the PML group are acknowledged for stimulating discussions and critical reading of the manuscript. M Gianni was supported by a grant from the `Ligue Nationale contre le Cancer' and FRM.
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Koken, M., Daniel, MT., Gianni, M. et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARα fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene 18, 1113–1118 (1999). https://doi.org/10.1038/sj.onc.1202414
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DOI: https://doi.org/10.1038/sj.onc.1202414
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