Mutations in Epigenetic Modifiers in Myeloid Malignancies and the Prospect of Novel Epigenetic-Targeted Therapy

Table 1

Translocations directly affecting histone modifying enzymes or recruitment of histone modifying enzymes in patients with myeloid malignancies.

Gene	Effects of translocation on histone posttranslational modifications
MLL1	MLL1 normally serves as an H3K4 methyltransferase. MLL-AF4, MLL-AF9, MLL-AF10, and MLL-ENL translocations result in loss of the SET domain and recruitment of DOT1L binding resulting in acquisition of H3K79 methyltransferase activity.
CBP	The histone acetyltransferase CBP has been reported to undergo translocation with MOZ in AML. This results in the disruption of CBP’s normal acetyltransferase activity and also in recruitment of CBP to MOZ-regulated gene promoters. MOZ also contains a putative acetyltransferase domain which may be affected in this translocation. CBP is also an occasional translocation partner with MLL1.
NSD1	The H3K36 methyltransferase NSD1 has been rarely reported to undergo translocation with NUP98 in AML. This translocation does not abrogate H3K36 methyltransferase activity of NSD1 but rather promotes aberrant H3K36 methylation at specific loci which promotes leukemogenesis.
P300	The histone acetyltransferase p300 is an occasional translocation partner with MLL1 in AML. This translocation preserves the majority of the coding sequence of p300, and the direct transcriptional and histone effects of this translocation are not well characterized. Interesting p300- and CBP-MLL translocations appear to be significantly associated with therapy-related AML rather than de novo AML suggesting a potential difference in the pathogenesis of these 2 subtypes of AML.
AML1	Translocations involving AML1 are characteristic of a proportion of patients with core-binding factor leukemias. Normally the C terminus of AML1 interacts with the histone acetyltransferase p300 and recruits p300 to specific loci bound by the N terminus of AML1. However, in the common translocation t(8;21)(q22;q22), the C terminus of AML1 is lost and replaced with the C terminus of ETO which attracts a corepressor complex with histone deacetylase activity (N-CoR/Sin3/HDAC complex).
RARα	The characteristic translocation of acute promyelocytic leukemia, t(15;17)(q21;q21) fuses PML with RARα. Recently it has been demonstrated that one of the critical aspects of PML-RARα-induced oncogenesis is aberrant downregulation of histone H3 acetylation by the PML-RARα fusion protein. Normally, in the presence of its ligand retinoic acid, RARα functions as a transcriptional activator. However, when ligand is not present, RARa functions as a transcriptional repressor through recruitment of HDACs. The PML-RARα fusion protein results in constitutive HDAC activity and aberrant target gene repression. Pharmacologic doses of ATRA appear to greatly increase histone H3 acetylation, and this, in part, serves to reverse some of the oncogenic effects of the PML-RARα fusion protein.