Mechanisms of epigenetic regulation of leukemia onset and progression

Abstract

Over the past decade, it has become clear that both genetics and epigenetics play pivotal roles in cancer onset and progression. The importance of epigenetic regulation in proper maintenance of cellular state is highlighted by the frequent mutation of chromatin modulating factors across cancer subtypes. Identification of these mutations has created an interest in designing drugs that target enzymes involved in DNA methylation and posttranslational modification of histones. In this review, we discuss recurrent genetic alterations to epigenetic modulators in both myeloid and lymphoid leukemias. Furthermore, we review how these perturbations contribute to leukemogenesis and impact disease outcome and treatment efficacy. Finally, we discuss how the recent advances in our understanding of chromatin biology may impact treatment of leukemia.

Figure 1.1

The role of DNA methylation in leukemia. (A) Wild-type IDH converts isocitrate to oxoglutarate. Mutations in IDH1 and 2 as found in myeloid leukemias change the activity of the enzyme. Mutant IDH converts oxoglutarate to 2-hydroxyglutarate. Oxoglutarate is a cofactor to dioxygenases like the TET proteins. TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine. This potentially leads to a demethylation of the DNA, which will permit transcription from a previously silent locus. (B) Overview of the effect of the different enzymes that regulate DNA methylation. When CpG islands are unmethylated, transcription can occur from that locus. (i) DNMT enzymes methylate CpG islands in the promoter, this leads to repression of transcription from this locus. (ii) TET proteins can oxidize the methylcytosine to 5-hydroxymethylcytosine. (iii) The outcome of this reaction is not yet fully understood, but it is suggested that this leads to demethylation permits transcription. (See Color Insert.)

Figure 1.2

Genetic perturbations impacting EZH2 and MLL proteins. (A) EZH2, the catalytic subunit of PRC2, represses gene activity by methylation of H3 on lysine 27. (B) Representative distribution of EZH2 mutations reported in T-ALL, myeloid disorders (MDS, MPN, CMML, AML), and DLBCL. (C) The wild-type MLL protein is the catalytic subunit of mammalian COMPASS-like complexes which enhances gene activity through methylation of H3 on lysine 4. MLL-fusion proteins frequently associate with members of DotCom to regulate methylation of H3 on lysine 79. (D) MLL-fusion proteins typically do not involve the Set methyltransferase domain but rather the N-terminal AT hooks and CxxC domain. Frequent MLL-fusion partners include AF-9, AF-4, and ENL. (See Color Insert.)

Figure 1.3

Major epigenetic modifiers that are genetically affected in leukemia, their associated marks and the corresponding inhibitors. (A) Major epigenetic modifiers with the corresponding inhibitors (marked with the letter i). Inhibitors that are being used for the treatment of hematopoietic malignancies are shown in red. HDAC (vorinostat and romidepsin) and DNMT inhibitors vidaza (5-azacytidine) and decitabine (5-aza-2-deoxycytidine) are currently used against MDS and CTCL correspondingly. Ruxolitinib is a JAK2 inhibitor used against myelofibrosis. HAT inhibitors, such as curcumin, have been used in clinical trials against leukemia and other hematopoietic malignancies. Other inhibitors used in the lab include histone (lysine), methyltransferase (KMTi) and demethylase (KDMi) inhibitors, and sirtuins inhibitors (SIRTi). (B) Recently, different combinations of different epigenetic inhibitors, as well as combinations of epigenetic inhibitors with drugs inhibiting signaling transduction pathways, or chemotherapy (such as alkylating agents) are being used in clinical trials. (See Color Insert.)