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Retinoic acid resistance in NB4 APL cells is associated with lack of interferon α synthesis Stat1 and p48 induction

Oncogene volume 18, pages 3944–3953 (1999)Cite this article

Abstract

In the t(15;17) acute promyelocytic leukaemia (APL), all trans-retinoic (RA) treatment induces maturation leading to clinically complete but not durable remission, as RA resistance develops in the treated patients as well as in vitro. RA and interferons (IFNs) are known inhibitors of proliferation in various cells including those from APL. In this report, we show that they can act cooperatively to inhibit growth and to induce differentiation of NB4 cells but not of two RA-resistant NB4 derived cell lines, NB4-R1 and NB4-R2. However, the resistant cell lines respond to IFN. In NB4 cells, RA increases the expression of Stat1, p48 and IRF-1, three transcription factors playing a central role in the IFN response and induces the synthesis and the secretion of IFNα. RA-induced IFNα seems to play a role in inhibition of NB4 cell growth but not in their differentiation. In the resistant cells, NB4-R1 and NB4-R2, both the induction of IFN and the increase of Stat1 and p48 expression by RA are completely blocked. In contrast, IRF-1 mRNA and protein expressions are induced in the three cell lines. This suggests that increase of IRF-1 expression is not sufficient for IFN induction. Our results identify some defects linked to RA-resistance in APL and support the hypothesis that RA-induced Stat1 expression and IFN secretion may be one of the mechanisms mediating growth inhibition by RA.

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Abbreviations

PML:

Pro-Myelocytic Leukemia-related gene/protein

APL:

Acute Promyelocyic Leukemia

RARα:

Retinoic Acid Receptor α

RA:

Retinoic Acid

IFN:

Interferon

NBs:

Nuclear Bodies

ISG:

IFN-Stimulated Gene

STAT:

Signal Transducers and Activators of Transcription

IRF:

Interferon Regulatory Factor (IRF)

ISGF3:

IFN-Stimulated Gene Factor 3

ISRE:

IFN-stimulated response element

GAS:

IFNγ-activated site

PKR:

RNA-dependent protein kinase

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Acknowledgements

We are grateful to H de Thé for helpful discussions and encouragements. We thank M Lanotte for supplying us with the acute promyelocytic cell lines NB4, NB4-R1 and NB4-R2. We acknowledge MC Guillemin for polyclonal anti-Sp100 antibodies, R Pine and C Schindler respectively for IRF-1 and Stat1 constructs. We are grateful to J Wietzerbin for the kind gift of the anti-human IFNα, β and γ antibodies and C Labonnardiere for Sendai virus. We thank C Chopin for technical assistance, M Lanotte, R Pine and A Saib for reading the manuscript. The help of B Boursin for the artwork were highly appreciated. This work was supported by grants from CNRS. L Pelicano was supported by Ligue contre le cancer fellowship.

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Authors and Affiliations

  1. CNRS, UPR 9051, Hópital St. Louis, Paris, 1 Avenue Vellefaux, Paris, Cedex 10, 75475, France

    Luis Pelicano, Caren Brumpt & Mounira K Chelbi-Alix

  2. Oncology Center, Johns Hopkins University, Baltimore, Maryland, 21231, MD, USA

    Paula M Pitha

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Pelicano, L., Brumpt, C., Pitha, P. et al. Retinoic acid resistance in NB4 APL cells is associated with lack of interferon α synthesis Stat1 and p48 induction. Oncogene 18, 3944–3953 (1999). https://doi.org/10.1038/sj.onc.1202802

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