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  • Review Article
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Targeting chromatin complexes in fusion protein-driven malignancies

Nature Reviews Cancer volume 19, pages 255–269 (2019)Cite this article

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Abstract

Recurrent chromosomal rearrangements leading to the generation of oncogenic fusion proteins are a common feature of many cancers. These aberrations are particularly prevalent in sarcomas and haematopoietic malignancies and frequently involve genes required for chromatin regulation and transcriptional control. In many cases, these fusion proteins are thought to be the primary driver of cancer development, altering chromatin dynamics to initiate oncogenic gene expression programmes. In recent years, mechanistic insights into the underlying molecular functions of a number of these oncogenic fusion proteins have been discovered. These insights have allowed the design of mechanistically anchored therapeutic approaches promising substantial treatment advances. In this Review, we discuss how our understanding of fusion protein function is informing therapeutic innovations and illuminating mechanisms of chromatin and transcriptional regulation in cancer and normal cells.

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Fig. 1: Chromatin-based mechanisms of fusion proteins.
Fig. 2: Indirect targeting of fusion protein function.
Fig. 3: Direct targeting of fusion protein function.

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Acknowledgements

The authors thank members of the Armstrong and Stegmaier laboratories for thoughtful discussions and feedback during the preparation of this manuscript. Work in the Armstrong laboratory is supported by grants from the US National Cancer Institute (CA176745, CA066996, CA204915 and CA231637) and Alex’s Lemonade Stand Foundation. Work in the Stegmaier laboratory is supported by US National Cancer Institute grants R35 CA210030 and R01 CA204915, US National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS088355 and US National Institutes of Health (NIH) grant U54 CA231637. Work in the Brien laboratory is supported by the Irish Cancer Society (CRF18BRI) and Science Foundation Ireland (18/SIRG/5573). Finally, the authors apologize to colleagues whose work we have been unable to discuss owing to space constraints.

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  1. Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland

    Gerard L. Brien

  2. Department of Pediatric Oncology, Dana Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Gerard L. Brien, Kimberly Stegmaier & Scott A. Armstrong

  3. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Kimberly Stegmaier

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G.L.B. wrote the manuscript with input from K.S. and S.A.A. All authors contributed to the discussion of content and reviewed and edited the manuscript.

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Correspondence to Gerard L. Brien or Scott A. Armstrong.

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Competing interests

S.A.A. is a consultant and/or shareholder for Epizyme, Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, Accent Therapeutics and Mana Therapeutics. K.S. has consulted for Novartis and Rigel Pharmaceuticals. The Armstrong laboratory has received research support from Janssen, Novartis and AstraZeneca. The Stegmaier laboratory receives grant support from Novartis. G.L.B. declares no competing interests.

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RELATED LINKS

COSMIC database: https://cancer.sanger.ac.uk/cosmic

Glossary

Nonspecific lethal

(NSL). A chromatin regulatory complex containing histone acetyltransferase activity, which is essential for eukaryotic development and gene expression.

SWI/SNF complexes

Major ATP-dependent chromatin remodellers that exploit the energy derived from ATP hydrolysis to regulate chromatin structure and genome accessibility.

Mediator

A modular, multi-protein complex required in eukaryotes for RNA polymerase II-mediated gene transcription.

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Brien, G.L., Stegmaier, K. & Armstrong, S.A. Targeting chromatin complexes in fusion protein-driven malignancies. Nat Rev Cancer 19, 255–269 (2019). https://doi.org/10.1038/s41568-019-0132-x

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