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Titolo:
Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RAR alpha and PLZF-RAR alpha oncoproteins
Autore:
Rego, EM; He, LZ; Warrell, RP; Wang, ZG; Pandolfi, PP;
Indirizzi:
Mem Sloan Kettering Canc Ctr, Dept Human Genet, Program Mol Biol, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA Mem Sloan Kettering Canc Ctr, Dept Med, Mol Therapeut Program, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 18, volume: 97, anno: 2000,
pagine: 10173 - 10178
SICI:
0027-8424(20000829)97:18<10173:RA(AAT>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
ARSENIC TRIOXIDE AS2O3; HISTONE DEACETYLASE COMPLEX; PML/RAR-ALPHA; MOLECULAR PATHOGENESIS; PROTEASOME PATHWAY; COMPLETE REMISSION; FUSION PROTEIN; CELL-LINES; NB4 CELLS; APOPTOSIS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Pandolfi, PP Mem Sloan Kettering Canc Ctr, Dept Human Genet, Program Mol Biol, 1275 York Ave, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr 1275 York Ave New York NY USA 10021
Citazione:
E.M. Rego et al., "Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RAR alpha and PLZF-RAR alpha oncoproteins", P NAS US, 97(18), 2000, pp. 10173-10178

Abstract

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RAR alpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes) in t(15;17) or t(11;17), respectively. APL in patients harboring t(15;17) responds well to retinoic acid (RA) treatment and chemotherapy, whereas t(11:17) APL responds poorly to both treatments, thus defining a distinct syndrome. Here, we show that RA, As2O3, and RA + As2O3 prolonged survival in either leukemic PML-RARalpha transgenic mice or nude mice transplanted with PML-RAR alpha leukemic cells. RA + As2O3 prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RAR alpha transgenic mice nor in nude mice transplanted with PLZF-RAR alpha cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RAand RA + As2O3 can induce, both in vivo and in vitro, the degradation of either PML-RAR alpha or PLZF-RAR alpha proteins, suggesting that the maintenance of the leukemic phenotype depends on the continuous presence of the former, but not the latter. Our findings lead to three major conclusions withrelevant therapeutic implications: (i) the X-RAR alpha oncoprotein directly determines response to treatment and plays a distinct role in the maintenance of the malignant phenotype; (ii) As2O3 and/or As2O3 + RA combination may be beneficial for the treatment of t(15;17) APL but not for t(11;17) APL; and (iii) therapeutic strategies aimed solely at degrading the X-RAR alpha oncoprotein may not be effective in t(11;17) APL.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 00:45:46