title: 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.
abstract: 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.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: D-C
authors.initials: DC
authors.lastname: Zhou
authors.forename: W
authors.initials: W
authors.lastname: Ding
authors.forename: E
authors.initials: E
authors.lastname: Paietta
authors.forename: F
authors.initials: F
authors.lastname: Guidez
authors.forename: A
authors.initials: A
authors.lastname: Zelent
authors.forename: K H
authors.initials: KH
authors.lastname: Ramesh
authors.forename: L
authors.initials: L
authors.lastname: Cannizzaro
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
authors.forename: R E
authors.initials: RE
authors.lastname: Gallagher
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007621:Karyotyping; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D020125:Mutation, Missense; D010087:Oxides / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D001152:Arsenicals; D016207:Cytokines; D010087:Oxides; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D019098:Telomerase; D000077237:Arsenic Trioxide