Epigenetic Modifiers in Normal and Malignant Hematopoiesis

Abstract

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.

Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer

“…Methylation of CpG islands in promoter regions is often associated with transcriptional silencing (34). However, methylation can occur outside of promoter CpG islands, and may not necessarily be correlated with gene silencing (34). DNA methyltransferase 3 alpha (DNMT3A) catalyzes the methylation of cytosine in CpG dinucleotides to 5-methylcytosine (5-mC).…”

“…DNA methyltransferase 3 alpha (DNMT3A) catalyzes the methylation of cytosine in CpG dinucleotides to 5-methylcytosine (5-mC). DNMT3A mutations are found in approximately 20% of patients with AML - the majority being heterozygous missense mutations altering the amino acid R882 (34). DNMT3A mutations are more common in CN-AML and are associated with older age and higher white blood cell count at diagnosis (34).…”

“…DNMT3A mutations are found in approximately 20% of patients with AML - the majority being heterozygous missense mutations altering the amino acid R882 (34). DNMT3A mutations are more common in CN-AML and are associated with older age and higher white blood cell count at diagnosis (34). The DNMT3A mutation reduces methyltransferase activity leading to focal hypomethylation by disrupting the ability of wildtype DNMT3A to form functional tetramers (35).…”

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

“…It mainly includes DNA methylation, histone modifications and microRNAs (miRNAs), which can, respectively, activate or silence gene transcription (or act post-transcriptionally in the case of miRNAs), leading to diverse functional effects. Indeed, complex roles have been reported for a variety of chromatin modifiers, including but not limited to DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACs) [7]. It is now evident that epigenetics plays crucial roles in many human diseases particularly cancer [8], especially in HCCs [9,10,11,12,13,14].…”

Touch, act and go: landing and operating on nucleosomes

“…Functional alterations in these complexes can lead to pathological conditions, such as developmental disorders and genetic syndromes, metabolic and immune system deregulation, aberrations in cell maturation and carcinogenesis (Jin et al, 2008;Lee et al, 2014;Rusconi et al, 2014;Tunovic et al, 2014;Haladyna et al, 2015;Mehdipour et al, 2015;Vallianatos & Iwase, 2015;Wang et al, 2015). Interestingly, many of the chromatin-modifying enzymes use metal (e.g.…”