A highlight of three recent studies focused on the evaluation of epigenomic alterations in myeloma cells, which may lead to the future development of therapeutics targeting novel epigenomic vulnerabilities in the disease.
Targeting epigenomic dependencies in multiple myeloma
Epigenome relates to DNA methylation, chromatin accessibility and histone modifications; its regulation is a critical mechanism of cell differentiation and oncogenesis. The advent of new technologies using next generation sequencing has exponentially improved our ability to study the cancer epigenome and may ultimately lead to new treatments.
In multiple myeloma, various epigenomic aberrations contribute to myelomagenesis and generate more than ten distinct molecular subgroups based on transcriptomic profiling (https://pubmed.ncbi.nlm.nih.gov/20574050/). This is exemplified by the histone methyl transferase (HMT) MMSET, which is universally overexpressed in the t(4;14) myeloma subgroup, or the histone acetyl transferase UTX/KDM6A, which is mutated in up to 5% of myeloma patients. Up to 24% of MM patients harbor at least one mutation in known epigenomic regulator genes (https://pubmed.ncbi.nlm.nih.gov/27235425/).
Moreover, aberrant DNA methylation is a classic feature of myeloma cells in comparison to normal plasma cells with a pattern of global hypomethylation and focal hypermethylation. Deeper characterization of the myeloma DNA methylation profile was recently reported by Dr Minvielle’s group and recently published in Genome Medicine (https://pubmed.ncbi.nlm.nih.gov/34372935/). In this study, the researchers used enhanced reduced representation bisulfite sequencing (eRRBS) technique to capture the methylation status of individual CpGs at the single allele and single cell levels in 42 primary myeloma samples. They observed significant intratumor heterogeneity identifying partially methylated domains along with methylation gains and losses featuring an “epigenomic instability”. Genes featured with bivalent promoters at CpG island were significantly enriched in oncogenesis pathways while genes with partially methylated domain were highly enriched in cell signaling pathways. While more longitudinal studies are needed to better characterize the DNS methylation profile evolution, these data reinforce our knowledge on DNA methylation contribution to myeloma progression and support future study that will investigate potentially targetable mechanisms involved in DNA methylation deregulation.
Along with aberrant DNA methylation, chromatin accessibility is another fundamental event participating to myeloma transcriptomic deregulation. Alvarez-Benayas et al. recently reported the chromatin accessibility landscape of 30 primary myeloma samples in comparison to 3 healthy donors plasma cells samples using Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) (https://pubmed.ncbi.nlm.nih.gov/34521827/). This method allows to precisely map chromatin accessibility genome-wide and to identify promoters and enhancers. The latter refers to DNA sequences usually but not necessary within a gene neighborhood that allows the binding of transcription factors which can modulate the given gene expression. Although this study included a limited number of samples, the investigators identified myeloma specific enhancers and super-enhancers leading to transcriptome deregulation and generating ultimately transcription factors dependencies.
Although specific targeting of transcription factors remains challenging, new methods using small molecules or degraders are under deep investigation and will likely be used in the next future in multiple myeloma. Such an example has been recently reported by Dr Ohguchi and colleagues (https://pubmed.ncbi.nlm.nih.gov/34258103/). In their study, the authors identified that Lysine demethylase 5A (KDM5A), which removes histone H3 lysine 4 di- and tri-methylation (H3K4me2 and H3K4me3) marks, contributes to maintain MYC-regulated genes active in myeloma cells. KDM5A was found to maintain MYC-regulated gene activity through its direct interaction with MYC but also independently of MYC through its direct interactions with CDK7 and CDK9 and their recruitment to specific MYC regulated genes. Moreover, using a specific KDM5A inhibitor, Dr Ohguchi and colleagues identified an efficient approach to abrogate MYC dependency and to target myeloma epigenome.
Thus, targeting aberrant methylation, chromatin accessibility and specific transcription factors dependencies constitute exciting research avenues that will ultimately change the therapeutic landscape of multiple myeloma.
