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Molecular Biology of APL

The impact of differential binding of wild-type RARα, PML-, PLZF- and NPM-RARα fusion proteins towards transcriptional co-activator, RIP-140, on retinoic acid responses in acute promyelocytic leukemia

Leukemia volume 14, pages 77–83 (2000)Cite this article

Abstract

Retinoic acid receptor (RA) heterodimer (RAR/RXR) activities have been shown to be repressed by transcriptional co-repressor, SMRT/N-CoR, in the absence of the ligand while upon all-trans retionic acid (ATRA) treatment, SMRT/N-CoR is dissociated from RARα leading to gene expression by the recruitment of transcriptional co-activators to the transcriptional complex. The difference in response to ATRA therapy between acute promyelocytic leukemia (APL) patients with PML-RARα fusion and PLZF-RARα fusion has recently been found to be partially due to the strong association of the transcriptional co-repressor, SMRT/N-CoR, with PLZF domain. We demonstrate that SMRT association, as with PML-RARα, can be released from NPM-RARα at pharmacological concentration of ATRA (10−6 M). Moreover, we show for the first time that the interaction between the transcriptional co-activator, RIP-140, and PML-, PLZF- or NPM-RARα fusion proteins can be positively stimulated by ATRA although they are less sensitive as compared with the wild-type RARα. Our results suggest that the dissociation of transcriptional co-repressors, SMRT/N-CoR, and recruitment of co-activators, eg RIP-140, to APL-associated fusion proteins constitute a common molecular mechanism in APL and underlie the responsiveness of the disease to RA therapy.

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Acknowledgements

We are indebted to Dr SW Morris, St Jude Children's Hospital, Memphis, TN, for kindly sending us the NPM-ALK plasmid, which was helpful in the construction of NPM-RARα expression plasmid. We thank Professor Zhu Chen, Shanghai Second Medical University and Dr A Zelent, LRF, London for helpful discussion. This work was supported by a RGC fundable-HKU block grant, 344-046-0001.

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  1. CW So and S Dong: The first two authors contributed equally to this work

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  1. Department of Pathology, The University of Hong Kong, Hong Kong, China

    CW So, CKC So & LC Chan

  2. Shanghai Transgenic Research Center, Shanghai, China

    S Dong & GX Cheng

  3. Shanghai Institute of Hematology, Shanghai Second Medical University, Shanghai, China

    QH Huang & SJ Chen

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So, C., Dong, S., So, C. et al. The impact of differential binding of wild-type RARα, PML-, PLZF- and NPM-RARα fusion proteins towards transcriptional co-activator, RIP-140, on retinoic acid responses in acute promyelocytic leukemia. Leukemia 14, 77–83 (2000). https://doi.org/10.1038/sj.leu.2401643

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