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-RARa and PLZF-RARα oncoproteins Journal Article

   

Authors:	Rego, E. M.; He, L. Z.; Warrell, R. P. Jr; Wang, Z. G.; Pandolfi, P. P.
Article Title:	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-RARa and PLZF-RARα oncoproteins
Abstract:	Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RARα 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-RARα transgenic mice or nude mice transplanted with PML-RARα leukemic cells. RA + As2O3 prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RARα transgenic mice nor in nude mice transplanted with PLZF-RARα cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RA and RA + As2O3 can induce, both in vivo and in vitro, the degradation of either PML-RARα or PLZF-RARα 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 with relevant therapeutic implications: (i) the X-RARα 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-RARα oncoprotein may not be effective in t(11;17) APL.
Keywords:	cancer survival; controlled study; unclassified drug; oncoprotein; nonhuman; antineoplastic agents; animal cell; mouse; animals; mice; apoptosis; protein degradation; neoplasm proteins; animal experiment; animal model; cell differentiation; transgenic mouse; animalia; mus musculus; mice, transgenic; arsenic trioxide; arsenicals; leukemia, promyelocytic, acute; oxides; nude mouse; mice, nude; leukemogenesis; acute myeloblastic leukemia; oncogene proteins, fusion; transplantation, heterologous; translocation, genetic; chromosomes, human, pair 11; retinoic acid; chromosomes, human, pair 17; chromosomes, human, pair 15; retinoic acid receptor; tretinoin; humans; priority journal; article; oncoprotein plzf; oncoproten pml
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	97
Issue:	18
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2000-08-29
Start Page:	10173
End Page:	10178
Language:	English
PUBMED:	10954752
PROVIDER:	scopus
PMCID:	PMC27786
DOI:	10.1073/pnas.180290497
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-0034730198&partnerID=40&md5=7e1c667dee63f5345d268e031a0cef6c
Notes:	Export Date: 18 November 2015 -- Source: Scopus

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