Common defects of different retinoic acid resistant promyelocytic leukemia cells are persistent telomerase activity and nuclear body disorganization Journal Article

  

Authors:	Nason-Burchenal, K.; Maerz, W.; Albanell, J.; Allopenna, J.; Martin, P.; Moore, M. A. S.; Dmitrovsky, E.
Article Title:	Common defects of different retinoic acid resistant promyelocytic leukemia cells are persistent telomerase activity and nuclear body disorganization
Abstract:	The acute promyelocytic leukemia (APL) t(15;17) rearrangement fuses the promyelocytic leukemia (PML) gene to the retinoic acid receptor-alpha (RARα). There is expression of the chimeric transcript, PML/RARα, in these APL cells. These clinical APL cases respond to the differentiation agent all-trans retinoic acid (ATRA) with complete but not durable remissions because ATRA resistance develops. The NB4 APL cell line expresses PML/RARα and responds to the growth inhibitory and differentiation-inducing signals of ATRA. To identify mechanisms responsible for ATRA resistance in APL, ATRA-resistant NB4 cell lines were derived from parental NB4 cells using different strategies. These lines were resistant to the growth inhibition and differentiation effects of ATRA. ATRA-resistant cells were isolated as a de novo resistant line from parental NB4 cells (NB4-R1), following chemical mutagenization and selection in ATRA (NB4-R2), or after chronic selection in ATRA (NB4-R3). Common defects linked to this ATRA resistance were found. When cultured in ATRA, these resistant cells still express PML, RARα, and PML/RARα proteins. Sequence abnormalities were not detected in the RARα DNA binding domains cloned from a representative RA-resistant NB4 line. In ATRA-sensitive but not ATRA-resistant NB4 cells, ATRA down-regulated retinoid X receptor-alpha (RXRα) expression, a known marker of ATRA response in parental NB4 cells. Notably, engineered overexpression of RXRα in ATRA-sensitive NB4 cells did not block ATRA-mediated growth suppression. ATRA treatment of these resistant NB4 lines did not signal a decline in telomerase activity or reorganization of PML-associated nuclear bodies, but both events occurred in ATRA-sensitive NB4 cells. These ATRA-resistant NB4 lines are not fully differentiation-defective, since monocytic maturation was induced following treatment with phorbol 12-myristate 13-acetate (PMA) and 1,25 dihydroxy vitamin D3 (vitamin D3). Notably, induced monocytic differentiation of these distinct ATRA-resistant APL lines markedly repressed telomerase activity. Thus, this study suggests that persistent telomerase activity and nuclear body disorganization are linked to ATRA resistance in APL.
Keywords:	controlled study; human cell; antineoplastic agents; polymerase chain reaction; protein domain; cell division; gene expression; cell maturation; cell differentiation; transcription, genetic; calcitriol; drug resistance; drug resistance, neoplasm; tumor cells, cultured; enzyme activity; telomerase; cancer resistance; molecular cloning; tumor suppressor gene; leukemia, promyelocytic, acute; blotting, western; cell culture; tumor cell line; dna, neoplasm; promyelocytic leukemia; down regulation; binding sites; cell nucleus; monocyte; retinoic acid; clone cells; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; carcinogens; cholecalciferol; retinoic acid receptor; tretinoin; receptors, retinoic acid; atra; cell nucleus inclusion body; chemical mutagenesis; humans; human; priority journal; article; methylnitronitrosoguanidine
Journal Title:	Differentiation
Volume:	61
Issue:	5
ISSN:	0301-4681
Publisher:	International Society of Differentiation
Date Published:	1997-09-01
Start Page:	321
End Page:	331
Language:	English
DOI:	10.1046/j.1432-0436.1997.6150321.x
PUBMED:	9342843
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0030826222&doi=10.1046%2fj.1432-0436.1997.6150321.x&partnerID=40&md5=cd3e1842fbecea9e8d71e3c43a0208fd
Notes:	Article -- Export Date: 17 March 2017 -- Source: Scopus

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