Chromatin modifiers and the promise of epigenetic therapy in acute leukemia

Abstract

Hematopoiesis is a tightly regulated process involving the control of gene expression that directs the transition from hematopoietic stem and progenitor cells to terminally differentiated blood cells. In leukemia, the processes directing self-renewal, differentiation and progenitor cell expansion are disrupted, leading to the accumulation of immature, non-functioning malignant cells. Insights into these processes have come in stages, based on technological advances in genetic analyses, bioinformatics and biological sciences. The first cytogenetic studies of leukemic cells identified chromosomal translocations that generate oncogenic fusion proteins and most commonly affect regulators of transcription. This was followed by the discovery of recurrent somatic mutations in genes encoding regulators of the signal transduction pathways that control cell proliferation and survival. Recently, studies of global changes in methylation and gene expression have led to the understanding that the output of transcriptional regulators and the proliferative signaling pathways are ultimately influenced by chromatin structure. Candidate gene, whole-genome and whole-exome sequencing studies have identified recurrent somatic mutations in genes encoding epigenetic modifiers in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). In contrast to the two-hit model of leukemogenesis, emerging evidence suggests that these epigenetic modifiers represent a class of mutations that are critical to the development of leukemia and affect the regulation of various other oncogenic pathways. In this review, we discuss the range of recurrent, somatic mutations in epigenetic modifiers found in leukemia and how these modifiers relate to the classical leukemogenic pathways that lead to impaired cell differentiation and aberrant self-renewal and proliferation.

Figure 1. Regulation of methylation and acetylation in leukemia and their therapeutic potential

The figure shows a selection of proteins that add, remove, and recognize chromatin modifications, as well as the the proteins that regulate DNA methylation. The genes encoding these proteins can be altered through mutation, deletion or altered expression in leukemia. Me, methylation; Ac, acetylation. DNMT, DNA methyltransferase; PKMT, lysine methyltransferase; KDM, lysine demethylase; PRMT, arginine methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase

Figure 2. Polycomb repressive complexes and MLL-fusion complexes in leukemia and their therapeutic potential

The PcG protein complexes, known as PRC1 and PRC2, maintain transcriptional silencing. EZH2 contains the methyltransferase activity for PRC2 that catalyzes the di and tri methylation of H3K27. Recurrent deletions and sequence mutations in EZH2, SUZ12, and EED are found in T-ALL. ASXL1 mutations promote transformation by decreasing PRC2 recruitment, and contributing to loss of transcriptional repression. Another PRC2 interacting protein, JAR1D2, is involved in the recruitment of the complex to target loci and is deleted in the progression of chronic phase myeloid malignancies to acute leukemia. PRC1 complex recognizes H3K27me3 via the chromodomain-containing CBX proteins and is involved in the maintenance of gene repression through histone H2A ubiquitination and the recruitment of DNA methyltransferases. PRC1 contains several proteins linked to cancer including Bmi-1, a protein associated with HSC self-renewal, and the ubiquitin ligases Ring1A and Ring1B. Several MLL fusion proteins can aberrantly recruit the DOT1L methyltranferase, leading to methylation of H3K79 and the activation of genes driving cellular transformation. MLL fusion proteins are also dependent on Menin, a component of the MLL-SET1-like histone methyltransferase complex and an adaptor to the chromatin associated protein LEDGF.