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

Y. Sun, S. H. Kim, D. C. Zhou, W. Ding, E. Paietta, F. Guidez, A. Zelent, K. H. Ramesh, L. Cannizzaro, R. P. Warrell, R. E. Gallagher

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16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1258-1269
Number of pages12
JournalLeukemia
Volume18
Issue number7
DOIs
StatePublished - Jul 2004

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Keywords

  • Acute promyelocytic leukemia
  • Arsenic trioxide resistance
  • Cell strain immortalization
  • Cytokine-dependent cell line
  • Retinoic acid resistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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