Epigenetics involves a heritable change in phenotype without a change in genotype–with the inheritance of particular chromatin and transcription states often underlying the mechanism. Chromatin regulates gene expression by controlling the density and positioning of nucleosomes, and by the use of histone- and DNA-modifying enzymes. Chromatin and transcription factors drive proper differentiation decisions through their coregulation of key factors in development and proliferation. Of particular interest to hematologists are instances when misregulation/mutation of chromatin factors drives hematologic malignancies and myeloproliferative disorders. Here, fusion proteins that involve the mistargeting of chromatin regulators have been known for decades. More recently, high-throughput sequencing and other genomics approaches have revealed mutations in many types of chromatin regulators in hematologic malignancies, including mutations in chromatin remodelers, DNA methylation regulators, histone modification enzymes, and metabolic enzymes affecting epigenetic cofactors. Overall, these studies reveal a consistent theme: epigenetic and genetic mutations confer both variation and plasticity to the transcriptome, and when combined with selection, arrive at transcriptomes that promote proliferation, survival, and adaptability. This chapter addresses these mechanistic principles of chromatin, and their misregulation in hematologic malignancies, as well as emerging therapeutic approaches.
Acronyms and Abbreviations:
AF, ALL1-fused gene; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BAF, BRG/BAF-associated factors; BCL, B-cell lymphoma family of regulator proteins that regulate cell death; BET, bromo and extraterminal; CHD, chromodomain remodeler; CMML, chronic myelomonocytic leukemia; DNAme, DNA methylation; DNMT, DNA methyltransferase; DOT1, a histone H3 methyltransferase; EGR1, early growth response protein 1; EZH2, enhancer of zeste homologue 2; H3, histone H3; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF, hypoxia-inducible transcription factor; 5hmC, 5-hydroxymethylcytosine; HMT, histone methyltransferase; HSC, hematopoietic stem cell; IDH, isocitrate dehydrogenase; Ifng promoter, interferon-γ promoter; ISWI, imitation SWI remodeler; MBD, methyl-domain binding; 5mC, 5-methylcytosine; MLL, mixed lineage leukemia; MTA, metastasis-associated; NuRD, nucleosome remodeling and deacetylation factor; NURF, nucleosome remodeling factor; 2OG, 2-oxoglutarate; PRC2, polycomb repressive complex 2; R-2HG, (R)-2-hydroxyglutarate; RAR, retinoic acid receptor; RNAP II, RNA polymerase II; SDH, succinate dehydrogenase; SRF, serum response factor; SWI/SNF, switch and sucrose nonfermenting remodeler; TDG, thymine DNA glycosylase; UHRF1, ubiquitin-like with PHD and ring finger domains; UTX, X-chromosome encoded ubiquitously transcribed tetratricopeptide repeat.
Epigenetics is defined as a heritable change in phenotype without a change in genotype. Although epigenetic mechanisms vary, this chapter focuses on the most common mechanism: chromatin. Changes in chromatin/epigenetics accompany many steps in transcription, replication, and recombination. However, the aspects of highest interest and relevance involve examples where epigenetic factors and enzymes drive differentiation decisions, and where misregulation/mutation of these factors drives pathologies, such as hematologic malignancies. This decision making must be precise, as differentiation along the lymphoid and myeloid lineages involves the regulated generation of multiple cell types in temporal order and proper proportion. Decisions are arrived through collaboration among signaling systems, transcription factors, and chromatin regulators-which together regulate the key genes governing self-renewal, differentiation, and survival. This chapter focuses on ...