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The biological significance of histone modifiers in multiple myeloma: clinical applications.

ABSTRACT: Multiple myeloma (MM) is a clonal plasma cell disorder that is characterized by a variety of genetic alterations. Recent studies have highlighted not only the importance of these genetic events but also epigenetic aberrations including DNA methylation, histone modifications, and non-coding RNAs in the biology of MM. Post-translational modifications of histone, such as methylation and acetylation, contribute to chromatin dynamics, and are modulated by histone modifying enzymes, and dysregulation of these enzymes is implicated in the pathogenesis of cancers, including MM. Histone modifiers also have non-histone substrates and enzymatically independent roles, which are also involved in tumorigenesis. Here we review and provide comprehensive insight into the biologic significance of histone methyl- and acetyl-modifiers in MM, and further provide an overview of the clinical applications of histone modifier inhibitors, especially histone deacetylase inhibitors. These findings underline the emerging roles of histone modifiers in the pathogenesis of MM, and further highlight the possibility of novel epigenetic therapies in MM.

SUBMITTER: Ohguchi H

PROVIDER: S-EPMC6127133 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The biological significance of histone modifiers in multiple myeloma: clinical applications.

Ohguchi Hiroto H Hideshima Teru T Anderson Kenneth C KC

Blood cancer journal 20180822 9

Multiple myeloma (MM) is a clonal plasma cell disorder that is characterized by a variety of genetic alterations. Recent studies have highlighted not only the importance of these genetic events but also epigenetic aberrations including DNA methylation, histone modifications, and non-coding RNAs in the biology of MM. Post-translational modifications of histone, such as methylation and acetylation, contribute to chromatin dynamics, and are modulated by histone modifying enzymes, and dysregulation ...[more]

PMID: 30190472

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Project description:In our previous studies, we identified 12 multiple myeloma (MM)-associated antigens by serological analysis of tumor-associated antigens with a recombinant cDNA expression library (SEREX) on MM. MM-associated antigen-8 (MMSA-8) was one of the new antigens identified. We determined the 3'- and 5'-ends of MMSA-8 using SMART-rapid amplification of cDNA ends (RACE) and then cloned its full-length cDNA in the U266 cell line. The full cDNA sequence revealed that MMSA-8 is RPS27A-related transcript variant 1 that is specifically associated with MM. We examined its prognostic significance for the first time, by investigating the correlations between MMSA-8 expression and definite clinicopathological features. We quantitatively assessed MMSA-8 expression using qRT-PCR and western blot analysis in healthy donors and MM patients. The expression levels of MMSA-8 were upregulated with statistical significance in MM patients in contrast to those in healthy donors. The expression of MMSA-8 was also upregulated in relapsed patients compared with that in the complete remission (CR) group. Contrasting MMSA-8 expression levels in different patients with definite clinicopathological features suggested an association between MMSA-8 with unfavorable clinicopathological characteristics, such as international staging system (ISS) stage III, higher lactate dehydrogenase (LDH) levels and higher C-reactive protein (CRP) levels. The expression of MMSA-8 was also increased in patients with unfavorable cytogenetic and genetic abnormalities, including the presence of t(11;14), t(4;14), t(14;16), del(17p), del(13q) and p53 deletion, which was statistically significant. The expression of MMSA-8 exhibited significant variance in the treatment responses of the CR, PR, progression and relapse groups. Univariate and multivariate analyses revealed that high MMSA-8 values were associated with poorer progression-free survival (PFS) and overall survival (OS) in MM patients independently. In conclusion, our data indicated that MMSA-8 is an independent and unfavorable prognostic risk factor in MM; MMSA-8 is also a promising diagnostic and therapeutic target in MM patients, but further validation is needed.

Dataset Information

The biological significance of histone modifiers in multiple myeloma: clinical applications.

Publications

The biological significance of histone modifiers in multiple myeloma: clinical applications.

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