Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control

Abstract

Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…EZH2 inhibitors exhibit strong anti‐MM effects alone or in combination with conventional treatments and other types of epigenetic inhibitors. Abnormal EZH2/H3K27me3 activity has been implicated in the pathogenesis of MM, and the degree of EZH2 overexpression correlates with the aggressiveness of MM subtypes and poor prognosis in MM patients . Homozygous mutations of EZH2 were described in myelodysplastic/myeloproliferative neoplasms but not in MM cell lines or primary patient cells .…”

Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

“…EZH2 is aberrantly overexpressed or subjected to gain‐of‐function mutations in various malignant tumors, including hematological malignancies . In MM, EZH2 is overexpressed and correlates not only with the development of asymptomatic monoclonal gammopathy of undetermined significance (MGUS) to active full‐blown myeloma but also with disease prognosis and poor survival, which emphasizes the importance of targeting EZH2 in the treatment of MM. Preclinical investigations on “selective” EZH2 inhibitors involved some of them in clinical trials against various tumors, including MM .…”

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

“…Recently, several EZH2-specific inhibitors have been developed, and pharmacologic inhibition of EZH2 by these inhibitors (E7438, UNC1999, GSK126, and EPZ005687) has been shown to exert anti-MM effects 48 , 54 , 57 – 60 . EZH2 inhibitors reduce global H3K27me3 level and trigger apoptosis in MM cells 48 , 54 , 57 – 60 . E7438 activates expression of epithelial tumor suppressor genes such as CDH1 , EMP1 , and EPHB2 , although the role of these genes in MM remains unclear 57 .…”

“…GSK126 also rescues osteoblast precursors from MM-induced suppression of osteoblast differentiation, suggesting that EZH2 inhibition may also be an effective treatment of lytic bone lesions in MM 61 . EPZ005687 upregulates cell cycle control genes, resulting in cell cycle arrest 48 .…”