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, Arthur Z Zelent, K. H. Ramesh, L. Cannizzaro, R. P. Warrell, R. E. Gallagher

Research output: Contribution to journalArticle

16 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Acute Promyelocytic Leukemia
Tretinoin
Cytokines
Cell Line
Ethylnitrosourea
Telomere Shortening
Recurrence
Cell Aging
Telomerase
COS Cells
Granulocyte Colony-Stimulating Factor
Missense Mutation
Metaphase
Karyotype
Drug Resistance
Transcriptional Activation
arsenic trioxide
Apoptosis
Ligands
Gene Expression

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

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

In: Leukemia, Vol. 18, No. 7, 07.2004, p. 1258-1269.

Research output: Contribution to journalArticle

Sun, Y, Kim, SH, Zhou, DC, Ding, W, Paietta, E, Guidez, F, Zelent, AZ, Ramesh, KH, Cannizzaro, L, Warrell, RP & Gallagher, RE 2004, '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', Leukemia, vol. 18, no. 7, pp. 1258-1269. https://doi.org/10.1038/sj.leu.2403372
Sun, Y. ; Kim, S. H. ; Zhou, D. C. ; Ding, W. ; Paietta, E. ; Guidez, F. ; Zelent, Arthur Z ; Ramesh, K. H. ; Cannizzaro, L. ; Warrell, R. P. ; Gallagher, R. E. / 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. In: Leukemia. 2004 ; Vol. 18, No. 7. pp. 1258-1269.
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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.",
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AU - Ding, W.

AU - Paietta, E.

AU - Guidez, F.

AU - Zelent, Arthur Z

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