Acute promyelocytic leukemia cell line AP-1060 established as a cytokine-dependent culture from a patient clinically resistant to all-trans retinoic acid and arsenic trioxide.
Fiche publication
Date publication
juillet 2004
Journal
Leukemia
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Sun Y, Kim SH, Zhou DC, Ding W, Paietta E, Guidez F, Zelent A, Ramesh KH, Cannizzaro L, Warrell RP, Gallagher RE
Lien Pubmed
Résumé
AP-1060 is a newly established acute promyelocytic leukemia (APL) cell line from a multiple-relapse patient clinically resistant to both all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The line was initially derived as a granulocyte colony-stimulating factor-dependent strain that underwent replicative senescence and, following ethylnitrosourea treatment, as a phenotypically similar immortalized line. Immortalization was associated with broadened cytokine sensitivity but not growth autonomy, in contrast to three previously derived APL lines. Both the AP-1060 strain and line had shortened telomeres and low telomerase activity, while the line had higher expression of many genes associated with macromolecular synthesis. The karyotype was 46,XY,t(3;14)(p21.1;q11.2),t(15;17)(q22;q11)[100%]; the unique t(3;14) was observed in 4/9 t(15;17)-positive metaphase cells at previous relapse on ATRA therapy. The PML-RARalpha mRNA harbored a missense mutation in the RARalpha-region ligand-binding domain (Pro900Ser). This was associated with a right-shift and sharpening of the ATRA-induced maturation response compared to ATRA-sensitive NB4 cells, which corresponded to the transcriptional activation by PML-RARalphaPro900Ser of a cotransfected ATRA-targeted reporter vector in COS-1 cells. AP-1060 also manifested relative resistance to ATO-induced apoptosis at >/=1 microM, while 0.25 microM ATO stimulated limited atypical maturation. These findings suggest that AP-1060 will be useful for further assessing molecular elements involved in APL progression and drug response/resistance.
Mots clés
Arsenic Trioxide, Arsenicals, pharmacology, Cell Culture Techniques, methods, Cell Line, Tumor, Cytokines, pharmacology, Drug Resistance, Neoplasm, Humans, Karyotyping, Leukemia, Promyelocytic, Acute, pathology, Mutation, Missense, Oxides, pharmacology, Receptors, Retinoic Acid, genetics, Retinoic Acid Receptor alpha, Telomerase, metabolism, Telomere, ultrastructure, Tretinoin, pharmacology
Référence
Leukemia. 2004 07;18(7):1258-69