Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

Abstract

Drug resistance (DR) of cancer cells leading to relapse is a huge problem nowadays to achieve long-lasting cures for cancer patients. This also holds true for the incurable hematological malignancy multiple myeloma (MM), which is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although new treatment approaches combining immunomodulatory drugs, corticosteroids, proteasome inhibitors, alkylating agents, and monoclonal antibodies have significantly improved median life expectancy, MM remains incurable due to the development of DR, with the underlying mechanisms remaining largely ill-defined. It is well-known that MM is a heterogeneous disease, encompassing both genetic and epigenetic aberrations. In normal circumstances, epigenetic modifications, including DNA methylation and posttranslational histone modifications, play an important role in proper chromatin structure and transcriptional regulation. However, in MM, numerous epigenetic defects or so-called 'epimutations' have been observed and this especially at the level of DNA methylation. These include genome-wide DNA hypomethylation, locus specific hypermethylation and somatic mutations, copy number variations and/or deregulated expression patterns in DNA methylation modifiers and regulators. The aberrant DNA methylation patterns lead to reduced gene expression of tumor suppressor genes, genomic instability, DR, disease progression, and high-risk disease. In addition, the frequency of somatic mutations in the DNA methylation modifiers seems increased in relapsed patients, again suggesting a role in DR and relapse. In this review, we discuss the recent advances in understanding the involvement of aberrant DNA methylation patterns and/or DNA methylation modifiers in MM development, progression, and relapse. In addition, we discuss their involvement in MM cell plasticity, driving myeloma cells to a cancer stem cell state characterized by a more immature and drug-resistant phenotype. Finally, we briefly touch upon the potential of DNA methyltransferase inhibitors to prevent relapse after treatment with the current standard of care agents and/or new, promising (immuno) therapies.

Keywords: DNA methylation modifiers; DNMTi; MM cell plasticity; epigenetics; multiple myeloma.

Figure 1

Schematic overview of the genetic and epigenetic abnormalities in MM. Primary (epi)genetic events are driving MM onset, while the secondary events are fostering MM progression and relapse. Primary genetic events include both hyperdiploid and non-hyperdiploid abnormalities, while primary epigenetic events are mainly characterized by global DNA hypomethylation and promotor specific hypermethylation of the tumor suppressors SOCS1 and DAPK. Secondary genetic events include non-recurrent secondary translocations, gain-of-function (GoF) mutations in oncogenes, and loss-of-function (LoF) mutations in tumor suppressor genes, while on the epigenetic level more pronounced global DNA hypomethylation and locus specific hypermethylation are observed together with increased (both global and locus specific) histone mark levels, including H3K27Ac, H3K4me1/3, H3K36me2/3, H3K27me3, and H4K20me3. The blue cell represents a normal plasma cell, while the purple and green cells represent respectively MM cells with primary and secondary events. The color gradation represents the increase in abnormalities in each stage. DSB, double strand breaks.

Figure 2

Schematic representation of the changes in global and gene specific DNA methylation patterns and DNA methylation modifiers in newly diagnosed and relapsed MM. In normal circumstances, CpG islands found in the promotor regions are in general not methylated, while the CpG dinucleotide in gene bodies, intergenic regions, and repetitive elements are mostly methylated. In MM, global hypomethylation is found in gene bodies, intergenic regions, and repetitive elements, while hypermethylation is observed in the CpG islands found in the promotor regions of tumor suppressor genes. In the relapsed settings, these events are even more pronounced. On the levels of the DNMT and TET enzymes, overexpression of DNMT1 and DNMT3B and loss-of-function (LoF) mutations in DNMT3A and TET2 are observed in newly diagnosed patients and the frequency of the LoF mutations in DNMT3A and TET2 are even further increased in the relapse setting. In healthy PCs, normal global methylation patterns are observed with a shift from the B-cell transcriptional program towards the PC specific transcriptional program, while in MM cells global hypomethylation leading to genomic instability and localized hypermethylation leading to silencing of tumor suppressor and B-cell specific genes are observed. PC, plasma cell.

Figure 3

Schematic overview of the structure of the DNMT and TET enzymes. The structure and different domains of (A) the five DNMT family members, DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L, and (B) the three TET family members, TET1, TET2, and TET3, are depicted. DMAP, DNA methyltransferase 1-associated protein binding domain; NLS, nuclear localization signal; RFTS, replication foci-targeting sequence; CXXC, Zn finger CXXC-domain; BAH, bromo-adjacent homology; GK, glycine-lysine repeat; MTase, methyl transferase; PWWP, proline-tryptophan-tryptophan-proline; ADD, ATRX-DNMT3A/B-DNMT3L; Cys, cysteine-rich domain; DSBH, double-stranded β-helix domain.