gsk-2816126 and 3-deazaneplanocin

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.

Topics: Adenosine; B-Lymphocytes; Cell Differentiation; Cell Proliferation; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Ethylenediamines; Gene Expression Regulation; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Histones; Humans; Indoles; Methylation; Polycomb Repressive Complex 2; Precision Medicine; Pyrazoles; Pyridones

Topics: Adenosine; Animals; Apoptosis; Benzazepines; Bile Ducts; Carbon Tetrachloride; Cell Cycle; Cell Cycle Proteins; Cell Line; Cell Proliferation; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Hepatic Stellate Cells; Humans; Indoles; Interleukin-10; Jumonji Domain-Containing Histone Demethylases; Ligation; Liver; Liver Cirrhosis; Mice; Pyridones; Pyrimidines; Rats; RNA Interference

Allogeneic hematopoietic cell transplantation is often complicated by graft versus host disease (GvHD), primarily mediated through allo-reactive donor T cells in the donor stem cell graft. Enhancer of Zeste Homolog 2 (EZH2), a histone-lysine N-methyltransferase and a component of the Polycomb Repressive Complex 2, has been shown to play a role in GvHD pathology. Although not yet clear, one proposed mechanism is through selective tri-methylation of lysine 27 in histone 3 (H3K27me3) that marks the promoter region of multiple pro-apoptotic genes, leading to repression of these genes in allo-reactive T cells. We found that selective pharmacologic inhibition of H3K27me3 with EPZ6438 or GSK126 did not prevent murine GvHD. This suggests the GvHD mitigating properties of DZNep are independent from H3K27me3 inhibition. Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required.

Topics: Adenosine; Animals; Benzamides; Biphenyl Compounds; Cells, Cultured; Disease Models, Animal; Enhancer of Zeste Homolog 2 Protein; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histone Code; Histones; Humans; Indoles; Methylation; Mice; Morpholines; Pyridones; T-Lymphocytes