Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development.
While the current epigenetic drug development is still largely restricted to target DNA methylome, emerging evidence indicates that histone methylome is indeed another major epigenetic determinant for gene expression and frequently deregulated in acute myeloid leukaemia (AML). The recent advances in dissecting the molecular regulation and targeting histone methylome in AML together with the success in developing lead compounds specific to key histone methylation-modifying enzymes have revealed new opportunities for effective leukaemia treatment. In this article, we will review the emerging functions of histone methyltransferases and histone demethylases in AML, especially MLL-rearranged leukaemia. We will also examine recent preclinical and clinical studies that show significant promises of targeting these histone methylation-modifying enzymes for AML treatment.
Leukaemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, Rayne Institute, London, UK.
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Leukaemia and Stem Cell Biology Group, Division of Cancer Studies, Department of Haematological Medicine, King's College London, Denmark Hill Campus, Rayne Institute, London, UK.
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D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000068456:Clinical Studies as Topic; D019175:DNA Methylation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D006657:Histones; D056466:Histone Demethylases; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase