cells Review Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation Florian Perner 1,2,* and Scott A. Armstrong 1 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; [email protected] 2 Internal Medicine II, Hematology and Oncology, Friedrich Schiller University Medical Center, 07747 Jena, Germany * Correspondence: fl[email protected] or [email protected]; Tel.: +1-857-407-9310 Received: 19 November 2020; Accepted: 20 December 2020; Published: 21 December 2020 Abstract: The aberrant function of chromatin regulatory networks (epigenetics) is a hallmark of cancer promoting oncogenic gene expression. A growing body of evidence suggests that the disruption of specific chromatin-associated protein complexes has therapeutic potential in malignant conditions, particularly those that are driven by aberrant chromatin modifiers. Of note, a number of enzymatic inhibitors that block the catalytic function of histone modifying enzymes have been established and entered clinical trials. Unfortunately, many of these molecules do not have potent single-agent activity. One potential explanation for this phenomenon is the fact that those drugs do not profoundly disrupt the integrity of the aberrant network of multiprotein complexes on chromatin. Recent advances in drug development have led to the establishment of novel inhibitors of protein–protein interactions as well as targeted protein degraders that may provide inroads to longstanding effort to physically disrupt oncogenic multiprotein complexes on chromatin. In this review, we summarize some of the current concepts on the role epigenetic modifiers in malignant chromatin states with a specific focus on myeloid malignancies and recent advances in early-phase clinical trials. Keywords: chromatin; EZH2; DOT1L; LSD1; Menin; MLL1; KMT2A; BRD4; BRD9; PPI; PROTAC; epigenetics; transcription; degradation; methylation; acetylation 1. Histone-Code and Epigenetic Networks: Implications for Myeloid Malignancies and Other Cancer Types The genomic DNA in eukaryotic cells is wrapped around a core histone octamer composed of Histone H2A (H2A), Histone H2B (H2B), Histone H3 (H3), and Histone H4 (H4) [1–3]. This complex of DNA and histones is compacted at different densities to chromatin, ranging from a simple chain of DNA and histones to highly condensed metaphase chromosomes [4–9]. The tight regulation of chromatin condensation and de-condensation is vital for a healthy organism since it is crucial for the equal distribution of genetic information to the daughter cells during cell division [10,11]. Furthermore, the state of chromatin condensation and therefore the degree of DNA accessibility, restricts or allows transcription factors and the RNA-polymerase machinery to physically interact with the DNA. Therefore, the stringent regulation of chromatin accessibility is a critical determinant of proper spatial and temporal regulation of gene transcription [12–14]. In cancer cells, the healthy chromatin homeostasis is disrupted by a variety of mechanisms promoting aberrant transcription and potentially also cytogenetic alterations [15–17]. The dynamics of chromatin biology are regulated by a variety of post-translational modifications at the unstructured core-histone tails [18]. These modifications involve methylation, acetylation, Cells 2020, 9, 2721; doi:10.3390/cells9122721 www.mdpi.com/journal/cells Cells 2020, 9, x 2 of 26 The dynamics of chromatin biology are regulated by a variety of post‐translational modifications Cells 2020, 9, 2721 2 of 26 at the unstructured core‐histone tails [18]. These modifications involve methylation, acetylation, and phosphorylation, as well as many other less well characterized modifications like sumoylation, ADP‐ andribosylation, phosphorylation, deimination, as well proline as many‐isomerization, other less and well crotonylation characterized [18–23]. modifications Early studies like sumoylation, in the field ADP-ribosylation,have provided evidence deimination, that histone proline-isomerization, acetylation, a andmark crotonylation that is broadly [18– 23associated]. 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Multiprotein Multiprotein-complexes‐complexes are recruited and/or and/or associate with reader proteins for locus specificspecific chromatin localization. In this example, the superelongation superelongation-complex,‐complex, which is required for RNAPolII activation, associates with BRD4. In actual physiological systems, the complexity of the protein protein-network‐network generated by the histone code is complicated, since the regulatory elements elements of of different different marks are highly interconnected. Writers andand eraserserasers of histonehistone modificationsmodifications get recruited by reader proteins of other histone modifications,modifications, leading to a topologically organized array of co co-existing‐existing modifications modifications and associated multi-proteinmulti‐protein complexes that define define distinct regulatory microenvironments at specific specific regions on chromatin impacting transcriptiontranscription andand 3D-chromosome3D‐chromosome architecturearchitecture [47[47–52].–52]. These regulatory networks areare central central mediators mediators of embryonic of embryonic development, development, lineage determination lineage determination during differentiation during and cellular homeostasis [53–65]. Consequently, aberrant regulation of this network is a hallmark Cells 2020, 9, 2721 3 of 26 of cancer development and progression [17,66–70]. Several of the recurrently detected genetic abnormalities in patients with myeloid malignancies involve epigenetic modifiers like DNMT3A, TET2, ASXL1, EZH2, IDH1/2, KMT2A, KAT6A, KDM5A, KDM6A, or NSD1 [71–74]. In the recent