Epigenetic modifiers in normal and malignant hematopoiesis.
Genome scale sequencing in patients with cancer has revealed a lower frequency of genetic aberrations in hematologic disorders compared with most other malignancies, suggesting a prominent role for epigenetic mechanisms. In parallel, epigenetic modifiers that are altered in cancer play critical roles in normal hematopoietic development, influencing both self-renewal of hematopoietic stem cells and differentiation into the different lineages. In this review, we aim to compare the role of several key DNA or histone modifying enzymes and complexes in normal development and hematopoietic malignancies, including DNMT3A, TET2, IDH1, IDH2, MLL1, MLL4, DOT1L, PRC1/2 and WSHC1/NSD2/MMSET. Insights into their biological mechanisms led to the development of therapies designed to target mutant IDH1 and IDH2, DOT1L in MLL-rearranged leukemias and EZH2 in several cancer types including lymphomas. Inhibitors for these enzymes are currently in clinical trials.
Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine & Children's Hospital Colorado, Aurora, CO 80045, USA.
Jessica N
JN
Haladyna
Taylor
T
Yamauchi
Tobias
T
Neff
Kathrin M
KM
Bernt
D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D019337:Hematologic Neoplasms / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C497422:KMT2A protein, human; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human; C473477:DOT1L protein, human; D008780:Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
DNMT3A; DOT1L; EZH2; IDH; MLL; PRC1/2; TET2; WSHC1/NSD2/MMSET; epigenetics; leukemia