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Histone Mutations and Bone Cancers

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Histone Mutations and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1283))

Abstract

Primary bone tumors are rare cancers that cause significant morbidity and mortality. The recent identification of recurrent mutations in histone genes H3F3A and H3F3B within specific bone cancers, namely, chondroblastomas and giant cell tumors of bone (GCTB), has provided insights into the cellular and molecular origins of these neoplasms and enhanced understanding of how histone variants control chromatin function. Somatic mutations in H3F3A and H3F3B produce oncohistones, H3.3G34W and H3.3K36M, in more than nine of ten GCTB and chondroblastomas, respectively. Incorporation of the mutant histones into nucleosomes inhibits histone methyltransferases NSD2 and SETD2 to alter the chromatin landscape and change gene expression patterns that control cell proliferation, survival, and differentiation, as well as DNA repair and chromosome stability. The discovery of these histone mutations has facilitated more accurate diagnoses of these diseases and stratification of malignant tumors from benign tumors so that appropriate care can be delivered. The broad-scale epigenomic and transcriptomic changes that arise from incorporation of mutant histones into chromatin provide opportunities to develop new and disease-specific therapies. In this chapter, we review how mutant histones inhibit SETD2 and NSD2 function in bone tumors and discuss how this information could lead to better treatments for these cancers.

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Abbreviations

CAF-1:

Chromatin assembly factor 1

DRD2:

Dopamine receptor D2

GCTB:

Giant cell tumor of bone

H3:

Histone 3

HIRA:

Histone regulator A

HMTase:

Histone methyltransferase

K:

Lysine

KDM:

Lysine demethylase

KMT:

Lysine methylation transferase

Me:

Methyl group

MMSET:

Multiple myeloma SET domain

NSD:

Nuclear receptor SET domain-containing

PRC2:

Polycomb-repressive complex 2

PRMT:

Protein arginine methyltransferases

PTM:

Posttranslational modification

RRM2:

Ribonucleotide reductase regulatory subunit M2

SETD:

Su(var)3-9, Enhancer of Zeste, Trithorax domain-containing

SRI:

Set2 Rpb1 interacting domain

WHSC1:

Wolf-Hirschhorn syndrome gene (aka, NSD2)

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Disclosures

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA

    Earnest L. Taylor & Jennifer J. Westendorf

Authors
  1. Earnest L. Taylor
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  2. Jennifer J. Westendorf
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Corresponding author

Correspondence to Jennifer J. Westendorf .

Editor information

Editors and Affiliations

  1. Institute of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China

    Dong Fang

  2. State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China

    Junhong Han

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Taylor, E.L., Westendorf, J.J. (2021). Histone Mutations and Bone Cancers. In: Fang, D., Han, J. (eds) Histone Mutations and Cancer. Advances in Experimental Medicine and Biology, vol 1283. Springer, Singapore. https://doi.org/10.1007/978-981-15-8104-5_4

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