期刊
LEUKEMIA
卷 18, 期 7, 页码 1258-1269出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2403372
关键词
acute promyelocytic leukemia; cell strain immortalization; cytokine-dependent cell line; retinoic acid resistance; arsenic trioxide resistance
资金
- NCI NIH HHS [CA56771, CA73136] Funding Source: Medline
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-RARalpha(omega) over bar -Pro900Ser of a cotransfected ATRA-targeted reporter vector in COS-1 cells. AP-1060 also manifested relative resistance to ATO-induced apoptosis at greater than or equal to1 muM, while 0.25 muM 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.
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