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International Journal of Hematology
Published in: International Journal of Hematology 3/2016

01-09-2016 | Progress in Hematology

Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma

Authors: Yusuke Furukawa, Jiro Kikuchi

Published in: International Journal of Hematology | Issue 3/2016

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Abstract

Multiple myeloma cells acquire the resistance to anti-cancer drugs through physical and functional interactions with the bone marrow microenvironment via two overlapping mechanisms. First, bone marrow stromal cells (BMSCs) produce soluble factors, such as interleukin-6 and insulin-like growth factor-1, to activate signal transduction pathways leading to drug resistance (soluble factor-mediated drug resistance). Second, BMSCs up-regulate the expression of cell cycle inhibitors, anti-apoptotic members of the Bcl-2 family and ABC drug transporters in myeloma cells upon direct adhesion [cell adhesion-mediated drug resistance (CAM-DR)]. Elucidation of the mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. Recent investigations, including ours, have revealed the involvement of epigenetic alterations in drug resistance especially CAM-DR. For example, we found that class I histone deacetylases (HDACs) determine the sensitivity of proteasome inhibitors and the histone methyltransferase EZH2 regulates the transcription of anti-apoptotic genes during the acquisition of CAM-DR by myeloma cells. In addition, another histone methyltransferase MMSET was shown to confer drug resistance to myeloma cells by facilitating DNA repair. These findings provide a rationale for the inclusion of epigenetic drugs, such as HDAC inhibitors and histone methylation modifiers, in combination chemotherapy for MM patients to increase the therapeutic index.
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Metadata
Title
Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma
Authors
Yusuke Furukawa
Jiro Kikuchi
Publication date
01-09-2016
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 3/2016
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2048-5

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