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Review
. 2016 Sep 15;30(18):2021-2041.
doi: 10.1101/gad.284109.116.

Epigenetics of hematopoiesis and hematological malignancies

Deqing Hu  1 , Ali Shilatifard  1   2
Affiliations
Review

Epigenetics of hematopoiesis and hematological malignancies

Deqing Hu et al. Genes Dev. .

Abstract

Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

Keywords: chromatin; epigenetics; hematopoiesis; histone.

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Figures

Figure 1.
Figure 1.
Hematopoietic systems in mammals. (A) Embryonic tissues of mouse hematopoietic development. Mouse hematopoietic activity arises from the mesoderm and first emerges in the extraembryonic yolk sac around E7.5 followed by the establishment of HSCs in AGM and the placenta around E.9.5. HSCs colonize the fetal liver around E12.5, migrate to the bone marrow before birth, and reside there throughout life. (B) Schematic overview of normal hematopoietic hierarchy in adult mice. HSCs sit at the top of the hierarchy and have both the capacity of self-renewal and the multipotent potential to give rise to all mature hematopoietic cell lineages. After receiving a differentiation signal, HSCs first lose self-renewing capacity and then progressively lose lineage potential, as they are restricted to a certain lineage. (LT-HSC) Long-term HSC; (ST-HSC) short-term repopulating HSC; (MPP) multipotent progenitor; (CMP) common myeloid progenitor; (CLP) common lymphoid progenitor; (LMPP) lymphoid-primed multipotent progenitor; (MEP) megakaryocyte/erythroid progenitor; (GMP) granulocyte-macrophage progenitor.
Figure 2.
Figure 2.
MLL translocation partners function in leukemogenesis. (A) Schematic representation of the domain structure of MLL and its stably associated cofactors in a COMPASS-like complex. MLL contains multiple domains essential for its biochemical and physiological function and is cleaved by Taspase I after aspartic acid 2718 to generate a large N-terminal fragment and a small C-terminal fragment, which subsequently associate noncovalently through FY-rich N-terminal (FYRN) and FY-rich C-terminal (FYRC) domains. (AT hook) Binds to the minor groove of AT-rich DNA sequences; (PHD) Plant homology domain; (SET) Su(var)3-9, enhancer of zeste, and trithorax domain. Core COMPASS subunits WDR5, RBBP5, ASH2L, and DPY30 interact with the SET domain, while Menin and HCF1 associate with more N-terminal regions. (B) Structure of the most frequent MLL chimeras in acute leukemia. A typical MLL fusion protein contains the N terminus of MLL and a C-terminal portion of one of >70 fusion partners. The AT hook and CXXC domains are retained in all MLL chimeras. (C) Two distinct complexes regulating transcription are made up of some of the most frequent MLL fusion partners: SEC (super elongation complex) and DotCom (DOT1L complex). SEC comprises the ELL family members ELL1, ELL2, and ELL3; the MLL translocation partners AF4/FMR2 family (AFF) member 1 (AFF1, also known as AF4) and AFF4; eleven-nineteen leukemia (ENL); the ALL1-fused gene from chromosome 9 (AF9); and the RNA polymerase II (Pol II) elongation factor P-TEFb (containing CDK9 and either cyclin T1 or cyclin T2). DotCom is composed of AF10, AF17, DOT1L, and AF9 or ENL. DOT1L is a methyltransferase specific for H3K79. (D) Therapeutic targeting of MLL translocated leukemia. MLL chimeras recruit SEC and/or DotCom to MLL target genes, which leads to their aberrant activation through misregulation of the transcriptional elongation checkpoint (Smith and Shilatifard 2013). Multiple therapeutic strategies have been developed to target different steps required for the activation of MLL chimera target genes in leukemia: MI503 blocks the association of Menin with MLL, potentially affecting recruitment of the MLL chimera to chromatin (indicated by a question mark); flavopiridol (FP) inhibits the kinase activity of SEC subunit P-TEFb; and EPZ-5676 is a small molecule blocking the enzymatic activity of DOT1L.
Figure 3.
Figure 3.
Misregulation of MLL3/4/COMPASS and polycomb group (PcG) proteins in hematopoietic transformation. (A) In normal HSCs and progenitors, MLL3/4/COMPASS and EZH2/PRC2 control the proper expression of genes involved in self-renewal and differentiation through implementation of H3K4me1 and H3K27me3 at enhancers. UTX, a component of the MLL3/MLL4/COMPASS-like complexes, harbors a demethylase activity specific for H3K27me3 that could antagonize transcriptional repression by the EZH2/PRC2 complex. (B) During lymphoma development, the catalytic subunit of PRC2, EZH2, is frequently mutated at Y641. This mutation results in a switch in substrate preference from nonmethylated to the monomethylated and dimethylated histone H3K27, leading to increased levels of H3K27 dimethylation (H3K27me2) and H3K27me3 at enhancers and promoters. Additionally, inactivating mutations in enhancer monomethyltransferases MLL3 and MLL4/COMPASS can cause loss of H3K4me1 at enhancers. Altogether, these events independently or together could lead to repression of enhancers and promoters of tumor suppressor genes to promote lymphomagenesis. (C) Schematic illustration of mammalian PRC1 and PRC2 complexes. PRC2 is composed of four core components—EED (embryonic ectoderm development), SUZ12 (suppressor of zeste 12 homolog), RBAP46, and RBAP48—and an enzymatic subunit, EZH1 or EZH2. EED and SUZ12 are essential for the stability of EZH1 and EZH2 and therefore for H3K27 methylation (Pasini et al. 2004; Xie et al. 2014). PRC1 complexes include both canonical and noncanonical forms in mammalian cells. Both canonical and noncanonical PRC1 complexes contain the catalytic subunit RING1A or RING1B that implements H2AK119 monoubiquitination. Canonical PRC1 complexes can variably include CBX2, CBX4, CBX7 or CBX8; BMI1 (also known as PCGF4) or MEL18 (also known as PCGF2); and PHC1, PHC2, or PHC3. The chromodomain found in the CBX proteins that participates in canonical PRC1 mediates the interaction with H3K27me3 that is catalyzed by PRC2. Noncanonical PRC1 complexes can contain RYBP or YAF2 and PCGF1, PCGF3, PCGF5, or PCGF6. (D) Inactivating mutations in MLL3, MLL4, UTX, and EZH2 were observed in myeloid leukemias (MDS, chronic myelomonocytic leukemia [CMML], and primary myelofibrosis [PMF]) and T-cell ALL (T-ALL). EZH1 can partially compensate for the loss of EZH2 in depositing H3K27me3 at enhancers and promoters. Loss of function of MLL3 and MLL4 removes H3K4me1 from enhancers, while UTX inactivation may increase H3K27me3 at the enhancers and promoters. All of these epigenetic alterations can collaborate to suppress the enhancers of tumor suppressor genes involved in myeloid leukemia and T-ALL. (E) In myeloid hematopoietic cells, ASXL1 (additional sex combs-like 1) promotes the repression of PRC2 targets via a currently unknown mechanism. (Top panel) Loss-of-function mutations of ASXL1 are frequently detected in CMML, MDS, and MPN, and these mutations could give rise to activation of an oncogene normally repressed by PRC2-mediated H3K27me3. (Bottom panel) BRCA1-associated protein 1 (BAP1) can function to attenuate the activity of PRC2. BAP1 loss results in increased expression of EZH2, which can result in myeloid transformation through the repression of tumor suppressor genes.
Figure 4.
Figure 4.
Misregulation of DNA methylation in hematological malignancies. (A) Dynamics of DNA methylation and demethylation mediated by DNA methyltransferase (DNMT3A, DNMT3B, and DNMT1) and Tet (ten-eleven translocation; TET1, TET2, and TET3) proteins. De novo DNA methyltransferases (DNMT3A and DNMT3B) add a methyl group to the fifth position of cytosine of CpG dinucleotides to form 5-methylcytosine (5mC) during embryonic development. During cell division, the maintenance DNA methyltransferase DNMT1 is targeted to hemimethylated CpG and adds a methyl group to the newly replicated DNA to faithfully maintain the DNA methylation pattern in daughter cells. DNA demethylation is achieved through active and passive pathways. In the active demethylation pathway, 5mC is successively oxidized by members of the TET family to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5caC is further converted to unmethylated cytosine via TDG (thymine DNA glycosylase)-mediated excision and subsequent replacement with unmethylated cytosine by the base excision repair (BER) mechanism. In addition, 5mC and its oxidized derivatives can be replaced with unmethylated cytosine during DNA replication (passive demethylation) if the maintenance DNA methylation is inhibited during DNA replication. (B). Inactivating mutations in DNMT3A and TET2 (red star) are likely to occur in preleukemic cells (multipotent HSCs or progenitors), which increase their self-renewal property and block differentiation. The acquisition of mutations in additional factors (green star) such as NPM and JAK eventually leads to the development of hematological malignancies.
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