Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs  Gerard L. Brien, Daria G. Valerio, Scott A. Armstrong  Cancer Cell  Volume 29, Issue 4, Pages 464-476 (April 2016) DOI: 10.1016/j.ccell.2016.03.007 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Chromatin Writers, Readers, and Erasers in Epigenetic Gene Regulation The addition of histone post-translational modifications is catalyzed by a class of enzymes known as chromatin “writers.” The modifications established by these writers (denoted by the orange circle) may affect gene transcription by altering electrostatic interactions within or between adjacent nucleosomes. Alternatively they may act as binding substrates for another class of chromatin regulators called chromatin “readers.” Chromatin readers employ characteristic binding domains, such as chromo-, bromo-, and PHD-finger domains to bind nucleosomes marked by specific modifications, or a combination of modifications. Chromatin readers may themselves possess additional chromatin-modifying activities, or alternatively recruit additional proteins to modify the local chromatin environment. Finally, chromatin “erasers” catalyze the removal of histone modifications, thereby reversing their biochemical effects on the chromatin fiber. Cancer Cell 2016 29, 464-476DOI: (10.1016/j.ccell.2016.03.007) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Targeting the Oncogenic Function of EZH2 in Lymphoma and Solid Tumors Heterozygous point mutations of the EZH2 SET domain in non-Hodgkin lymphomas lead to an enhanced accumulation of H3K27me3 on the promoters of PRC2 target genes in germinal center B cells (upper panel). This causes aberrant silencing of these genes, many of which are required for terminal B cell differentiation and cell-cycle exit. Small-molecule inhibitors (right panels) of EZH2 enzymatic activity are currently in clinical trials for the treatment of lymphoma patients with activating EZH2 mutations. Moreover, these molecules are also in trials for the treatment of SNF5-deficient malignant rhabdoid tumors (MRTs) where SNF5 loss facilitates aberrant EZH2-mediated silencing of SNF5 target genes, such as the tumor suppressor CDKN2A (lower panel). Cancer Cell 2016 29, 464-476DOI: (10.1016/j.ccell.2016.03.007) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Targeting MLL-Rearranged Leukemia through Co-opted DOT1L Activity Studies have demonstrated that MLL-fusion proteins, such as MLL-AF9, recruit aberrant chromatin activity in the form of DOT1L-mediated H3K79me2 to the promoter of MLL-fusion target genes in primitive hematopoietic cells. DOT1L activity is essential for the expression of MLL-fusion target genes such as HOXA9 and MEIS1, and this requirement has been exploited through the development of small-molecule inhibitors of DOT1L enzymatic activity (right panel). DOT1L inhibitors are currently in clinical trials for the treatment of MLL-rearranged leukemia. Cancer Cell 2016 29, 464-476DOI: (10.1016/j.ccell.2016.03.007) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 Defining the Epigenomic Changes in Cancer The alteration of a single chromatin-modifying activity in cancer cells is known to have profound effects on the landscape of additional related chromatin modifications and other chromatin regulators. These alterations are likely instrumental in disease pathogenesis; however, until recently our ability to systematically annotate such changes has been limited. The use of unbiased quantitative mass spectrometry techniques holds great promise for the annotation of chromatin dynamics in response to cancer-promoting alterations in epigenetic pathways. This may facilitate the identification of additional therapeutic targets within the cancer epigenome. Cancer Cell 2016 29, 464-476DOI: (10.1016/j.ccell.2016.03.007) Copyright © 2016 Elsevier Inc. Terms and Conditions