| 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-RARα mRNA harbored a missense mutation in the RARα-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-RARαω Prog900Ser of a cotransfected ATRA-targeted reporter vector in COS-1 cells. AP-1060 also manifested relative resistance to ATO-induced apoptosis at ≥ 1 μM, while 0.25 μM 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. © 2004 Nature Publishing Group All rights reserved. |
| Keywords: |
controlled study; human cell; genetics; missense mutation; mutation, missense; methodology; antineoplastic agent; phenotype; telomere; metabolism; cell viability; reverse transcription polymerase chain reaction; apoptosis; gene expression profiling; transcription initiation; cancer cell culture; drug resistance; pathology; drug resistance, neoplasm; enzyme activity; cell line, tumor; telomerase; arsenic trioxide; arsenicals; leukemia, promyelocytic, acute; oxides; cytokine; cytokines; messenger rna; leukemia cell; tumor cell line; promyelocytic leukemia; cell culture techniques; chromosome translocation; immunophenotyping; dna microarray; culture technique; concentration (parameters); chromosome analysis; karyotyping; granulocyte colony stimulating factor; retinoic acid; ultrastructure; ligand binding; ethylnitrosourea; metaphase; acute promyelocytic leukemia; retinoic acid receptor alpha; retinoic acid receptor; cell immortalization; tretinoin; receptors, retinoic acid; organoarsenic derivative; oxide; humans; human; priority journal; article; arsenic trioxide resistance; cell strain immortalization; cytokine-dependent cell line; retinoic acid resistance; karyotype 46,xy
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