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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 volume 18, pages 1258–1269 (2004)Cite this article

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-RARαPro900Ser of a cotransfected ATRA-targeted reporter vector in COS-1 cells. AP-1060 also manifested relative resistance to ATO-induced apoptosis at ⩾1 μ M, while 0.25 μ M 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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Acknowledgements

We thank Dr Michel Lanotte for providing NB4 cells, Drs Malcolm Moore and John Mori for providing MS-5 cells, Amgen, Immunex and the Genetics Institute for providing hematopoietic growth factors, Drs William Hahn and Warren Pear for providing mammalian expression vectors, Drs John Mariadason and Leonard Augenlicht, Mr Matthew Friedman and the Albert Einstein Microarray Core Laboratory for assistance with the analyses of cDNA microarray experiments, the Albert Einstein Flow Cytometry Core Laboratory for assistance with analyses of apoptosis/cell cycle experiments, and Ms Serena Mak for assistance in preparation of the manuscript figures.

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  1. Y Sun and S H Kim: These authors contributed equally to the work in this manuscript

Authors and Affiliations

  1. Department of Oncology, Montefiore Medical Center, Bronx, NY, USA

    Y Sun, S H Kim, D-C Zhou, W Ding & R E Gallagher

  2. Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY, USA

    E Paietta

  3. Leukaemia Research Fund, Chester Beatty Laboratories, London, UK

    F Guidez & A Zelent

  4. Department of Pathology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA

    K H Ramesh & L Cannizzaro

  5. Department of Medicine, Developmental Chemotherapy and Leukemia Services, Memorial Sloan-Kettering Cancer Center and the Cornell University Medical College, New York, NY, USA

    R P Warrell Jr

  6. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    R E Gallagher

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Supported by grants from the National Institutes of Health (CA56771(REG) and CA73136 (RPW)) and the Leukaemia Research Fund of Great Britain (AZ).

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Sun, Y., Kim, S., Zhou, DC. et al. 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 18, 1258–1269 (2004). https://doi.org/10.1038/sj.leu.2403372

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