Gabriella Webster

Introduction. Despite being the second most common hematologic cancer which accounts for 10% of all hematological malignancies, Multiple Myeloma is a currently incurable, genetically heterogeneous plasma cell neoplasm with a complex underlying mechanism that is poorly understood.^1-3 While Multiple Myeloma is associated with specific genetic mutations and instabilities, the possible impact of epigenetic aberrations on tumorigenesis should not be overlooked.⁴ In fact, there is evidence that Multiple Myeloma B cells have epigenetic configurations that differ from normal B cells at every layer of the epigenome, including histone modification of chromatin.³ Acetylation on lysine residues of histones activates DNA transcription and replication by changing chromatin structure to allow transcription and replication machinery to access DNA.⁵ These changes are often gain-of-function and lead to increased expression of Multiple Myeloma associated genes due to more accessible chromatin.3 Results. There are a number of recent discoveries regarding the role of histone modification in Multiple Myeloma and ways to target histone modification in Multiple Myeloma treatment. 806 sites of mutation have been identified in H3K27ac (an epigenetic modification to the DNA packaging protein Histone H3) alone which increase chromatin accessibility compared to normal B cells.³ These sites contain binding motifs of numerous transcription factor families which are linked to Multiple Myeloma pathogenesis, and inhibition of these transcription factor families as a treatment strategy for Multiple Myeloma is currently being explored.³ Additionally, 24 proteins have been identified which interact with a histone methyltransferase (NSD2) that is upregulated in t(4;14) Multiple Myeloma, including the DNA damage regulator PARP1.⁶ This reveals that there is a connection between PARylation and histone methylation in Multiple Myeloma pathogenesis.⁶ Finally, hedgehog signaling, activated by SIRT1, has been shown to be upregulated in Multiple Myeloma cells that have developed resistance to the proteasome inhibitor, Bortezomib, which is commonly used to treat Multiple Myeloma.² This indicates that SIRT1 inhibitors used in combination with proteasome inhibitors may be useful in treating drug resistant Multiple Myeloma.² Histone deacetylase inhibitors such as LMK-235, which induces apoptosis in Multiple Myeloma cells through HO-1, may also be prove useful in treating Multiple Myeloma, in addition to polyphenols like Oleacin, which has been shown to have an inhibitory effect on Multiple Myeloma cell survival by upregulating histone acetylation and downregulating some histone deacetylases in a dose-dependent manner.^5,7

1. Caprio C, Sacco A, Giustini V, Roccaro AM. Epigenetic aberrations in multiple myeloma. Cancers. 2020;12(10):2996. doi:10.3390/cancers12102996
2. Xie Y, Liu J, Jiang H, et al. Proteasome inhibitor induced SIRT1 deacetylates GLI2 to enhance hedgehog signaling activity and drug resistance in multiple Oncogene. 2019;39(4):922-934. doi:10.1038/s41388-019-1037-6
3. Ordoñez, Raquel, et “Chromatin Activation as a Unifying Principle Underlying Pathogenic Mechanisms in Multiple Myeloma.” 2019, doi:10.1101/740027.
4. Cypris O, Božić T, Wagner Chicken or Egg: Is Clonal Hematopoiesis Primarily Caused by Genetic or Epigenetic Aberrations? Frontiers in Genetics. 2019;10. doi:10.3389/fgene.2019.00785
5. Li, Xinyao, et al. “Histone Deacetylase Inhibitor LMK-235-Mediated HO-1 Expression Induces Apoptosis in Multiple Myeloma Cells via the JNK/AP-1 Signaling ” Life Sciences, vol. 223, 2019, pp. 146–157., doi:10.1016/j.lfs.2019.03.011.
6. Huang, Xiaoxiao, et al. “Defining the NSD2 Interactome: PARP1 PARylation Reduces NSD2 Histone Methyltransferase Activity and Impedes Chromatin ” Journal of Biological Chemistry, vol. 294, no. 33, 2019, pp. 12459–12471., doi:10.1074/jbc.ra118.006159.
7. Juli, Giada, et “Anti-Tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma.” Cancers, vol. 11, no. 7, 2019, p. 990., doi:10.3390/cancers11070990.