Deregulated Polycomb functions in myeloproliferative neoplasms

Goro Sashida; Motohiko Oshima; Atsushi Iwama

doi:10.1007/s12185-019-02600-6

Deregulated Polycomb functions in myeloproliferative neoplasms

Int J Hematol. 2019 Aug;110(2):170-178. doi: 10.1007/s12185-019-02600-6. Epub 2019 Jan 31.

Authors

Goro Sashida¹, Motohiko Oshima², Atsushi Iwama³

Affiliations

¹ Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
² Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
³ Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. 03aiwama@ims.u-tokyo.ac.jp.

PMID: 30706327
DOI: 10.1007/s12185-019-02600-6

Abstract

Polycomb proteins function in the maintenance of gene silencing via post-translational modifications of histones and chromatin compaction. Genetic and biochemical studies have revealed that the repressive function of Polycomb repressive complexes (PRCs) in transcription is counteracted by the activating function of Trithorax-group complexes; this balance fine-tunes the expression of genes critical for development and tissue homeostasis. The function of PRCs is frequently dysregulated in various cancer cells due to altered expression or recurrent somatic mutations in PRC genes. The tumor suppressive functions of EZH2-containing PRC2 and a PRC2-related protein ASXL1 have been investigated extensively in the pathogenesis of hematological malignancies, including myeloproliferative neoplasms (MPN). BCOR, a component of non-canonical PRC1, suppresses various hematological malignancies including MPN. In this review, we focus on recent findings on the role of PRCs in the pathogenesis of MPN and the therapeutic impact of targeting the pathological functions of PRCs in MPN.

Keywords: ASXL1; BCOR; BRD4 inhibition; DNA methylation; EZH2.

Publication types

Review

MeSH terms

Cell Cycle Proteins / physiology
Cell Transformation, Neoplastic / genetics*
Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein / deficiency
Enhancer of Zeste Homolog 2 Protein / physiology
Gain of Function Mutation
Gene Expression Regulation, Neoplastic
Hematopoiesis
Histone Code
Histone-Lysine N-Methyltransferase / physiology
Humans
Molecular Targeted Therapy
Myeloid-Lymphoid Leukemia Protein / physiology
Myeloproliferative Disorders / genetics*
Myeloproliferative Disorders / metabolism
Neoplasm Proteins / deficiency
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Polycomb Repressive Complex 2 / antagonists & inhibitors
Polycomb-Group Proteins / deficiency
Polycomb-Group Proteins / genetics
Polycomb-Group Proteins / physiology*
Proto-Oncogene Proteins / physiology
Repressor Proteins / physiology
Transcription Factors / physiology

Substances

ASXL1 protein, human
BCOR protein, human
BRD4 protein, human
Cell Cycle Proteins
KMT2A protein, human
Neoplasm Proteins
Polycomb-Group Proteins
Proto-Oncogene Proteins
Repressor Proteins
Transcription Factors
Myeloid-Lymphoid Leukemia Protein
EZH1 protein, human
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Histone-Lysine N-Methyltransferase
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding