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Malignant lymphomas are a group of diseases in which epigenomic abnormalities are fundamental to the pathogenesis and pathophysiology and are characterized by a high frequency of abnormalities in DNA methylation regulators and histone modifiers. These epigenomic abnormalities directly amplify malignant clones. They also originated from a cell lineage differentiated from hematopoietic stem cells through epigenomic changes. These characteristics are associated with their high affinity for epigenomic therapies. Hematology has been a leader in the basic, clinical, and drug discovery areas of disease epigenetics. However, the epigenomic regulation is generally recognized as a complex system, and gaps are observed between basic and clinical studies. To overview the status and importance of "epigenomic abnormalities in malignant lymphoma," this review first summarizes the concept and essential importance of the epigenome and then outlines the current status and future perspective of epigenomic abnormalities in malignant lymphomas.

Genes that regulate immunological activities are transiently suppressed by epigenetic modification during the germinal center reaction of B cells and reactivated when B cells exit the germinal center. Mutations of EZH2 and other epigenetic modifier genes are frequently involved in the pathogenesis of follicular lymphoma and lead to silencing of the genes necessary for exiting the germinal center. Tazemetostat, an EZH2 inhibitor, has been approved for the treatment of follicular lymphoma with EZH2 gain-of-function mutations in Japan. Tazemetostat restores the expressions of MHC and CD58 in lymphoma cells and synergistically enhances the immune reactions of T and natural killer cells against lymphoma cells. Tazemetostat also induces lymphoma cells to secrete CCL17/TARC and enhances T-cell migration. CD58 and CCL17 are known to play central roles in the formation of T-cell-rich tumor microenvironment of Hodgkin lymphoma. We found that tazemetostat enhances the expression of genes overexpressed in Hodgkin/Reed-Sternberg cells. Epigenetic modifiers and new molecular targeted therapies are expected to provide new insights into the pathogenesis of lymphoma and mechanisms determining the histology of lymphoma.

Histone H3 lysine 27 tri-methylation (H3K27me3) -dependent transcription regulation is a fundamental process of gene control. Although EZH2 mutation is observed in certain lymphoma types, many other cancers show global H3K27me3 accumulation irrespective of mutation. However, the underlying mechanisms of gene silencing and therapeutic efficacies of epigenetic drugs remain unclear. In this study, we showed that globally-accumulated H3K27me3 is induced by both cis-bound EZH1 and EZH2 in mature lymphocyte-derived malignancies. Mutual interference and compensatory functions of co-expressed EZH1/2 rearrange the genome-wide distribution, establishing restricted chromatin and gene expression signatures. Using novel EZH1/2 dual inhibitors, we found that both EZH1 and EZH2 are required for the maintenance and induction of H3K27me3. The synthetic lethality of targeting EZH1 and EZH2 was observed in lymphoma models and primary adult T-cell leukemia/lymphoma (ATL) cells harboring H3K27me3 accumulation. This heritable EZH1/2 dysfunctional state was epigenetically imprinted at the virus-infected, immortalized phase. EZH1/2 dual inhibition could eliminate infected cell populations more effectively than EZH2 inhibition. Regarding the frequent observation of H3K27me3 accumulation in advanced-stage and early-phase malignant progenitors, the emerging EZH1- and EZH2-dependent epigenetic reprograming is an incipient process of fate decision within developmental pathways of cancers.

Myeloproliferative neoplasms (MPNs) are characterized by the activation of the JAK-STAT pathway due to driver mutations, including JAK2V617F, but some additional abnormalities may be necessary to maintain an MPN clone and develop a more advanced disease. The HMGA2 proto-oncogene, which regulates the expression of various genes, is often overexpressed due to downregulation of let-7 microRNAs or EZH2 mutations in advanced MPNs such as myelofibrosis. In mice with JAK2V617F, Ezh2 deletion deregulates Hmga2, which plays a crucial role in MPN progression. Correspondingly, Hmga2 overexpression causes massive splenomegaly and severe anemia in mice carrying JAK2V617F, mimicking severe MPN. Herein, we discuss the mechanisms of HMGA2 deregulation and its possible use as a therapeutic target.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Epigenetic regulators, including TET2, DNMT3A and EZH2, are often mutated in patients with MDS. Recently, exome sequencing of blood cells from aged people without hematological malignancies have demonstrated the presence of clonal hematopoiesis with myeloid malignancies-associated mutations, such as TET2 and DNMT3A. Here, I will discuss the molecular mechanisms underlying the accumulation of epigenetic alterations and genetic mutations, including TET2, DNMT3A and EZH2, and how these promote the development of MDS and hematological malignancies in aged people with clonal hematopoiesis.