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Christopher R. Vakoc

Yusuke Tarumoto, Bin Lu, Tim D D Somerville, Yu-Han Huang, Joseph P Milazzo, Xiaoli S Wu, Olaf Klingbeil, Osama El Demerdash, Junwei Shi, Christopher R Vakoc
The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF...
February 28, 2018: Molecular Cell
Ana Banito, Xiang Li, Aimée N Laporte, Jae-Seok Roe, Francisco Sanchez-Vega, Chun-Hao Huang, Amanda R Dancsok, Katerina Hatzi, Chi-Chao Chen, Darjus F Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B Jones, Mario R Capecchi, Christopher R Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O Nielsen, Scott W Lowe
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands...
February 22, 2018: Cancer Cell
Anand S Bhagwat, Bin Lu, Christopher R Vakoc
Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell and, conversely, knowledge of the enhancer configuration can be used to discover functionally important TFs in a given cellular process...
February 9, 2018: Blood
Yali Xu, Joseph P Milazzo, Tim D D Somerville, Yusuke Tarumoto, Yu-Han Huang, Elizabeth L Ostrander, John E Wilkinson, Grant A Challen, Christopher R Vakoc
Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis...
January 8, 2018: Cancer Cell
Isaia Barbieri, Konstantinos Tzelepis, Luca Pandolfini, Junwei Shi, Gonzalo Millán-Zambrano, Samuel C Robson, Demetrios Aspris, Valentina Migliori, Andrew J Bannister, Namshik Han, Etienne De Braekeleer, Hannes Ponstingl, Alan Hendrick, Christopher R Vakoc, George S Vassiliou, Tony Kouzarides
N6 -methyladenosine (m6 A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice...
December 7, 2017: Nature
Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A Davies, Christopher R Vakoc, Eva Hernando, Emily Bernstein
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2...
November 16, 2017: Molecular Cell
Christopher R Vakoc, David A Tuveson
<b/> Pathways that stimulate metastasis of pancreatic cancer cells are critical for understanding tumor evolution and can serve as potential therapeutic targets. The microenvironment produces a host of metabolic perturbations and tropic factors that may play a formative role in this process. Cancer Discov; 7(10); 1067-8. ©2017 AACR. See related article by Chiou et al., p. 1184 .
October 2017: Cancer Discovery
Jae-Seok Roe, Chang-Il Hwang, Tim D D Somerville, Joseph P Milazzo, Eun Jung Lee, Brandon Da Silva, Laura Maiorino, Hervé Tiriac, C Megan Young, Koji Miyabayashi, Dea Filippini, Brianna Creighton, Richard A Burkhart, Jonathan M Buscaglia, Edward J Kim, Jean L Grem, Audrey J Lazenby, James A Grunkemeyer, Michael A Hollingsworth, Paul M Grandgenett, Mikala Egeblad, Youngkyu Park, David A Tuveson, Christopher R Vakoc
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo...
August 24, 2017: Cell
Bryan R Lanning, Christopher R Vakoc
No abstract text is available yet for this article.
April 11, 2017: Nature Biotechnology
Jonathan J Ipsaro, Chen Shen, Eri Arai, Yali Xu, Justin B Kinney, Leemor Joshua-Tor, Christopher R Vakoc, Junwei Shi
Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors...
2017: PloS One
Yali Xu, Christopher R Vakoc
Cancer cells are often hypersensitive to the targeting of transcriptional regulators, which may reflect the deregulated gene expression programs that underlie malignant transformation. One of the most prominent transcriptional vulnerabilities in human cancer to emerge in recent years is the bromodomain and extraterminal (BET) family of proteins, which are coactivators that link acetylated transcription factors and histones to the activation of RNA polymerase II. Despite unclear mechanisms underlying the gene specificity of BET protein function, small molecules targeting these regulators preferentially suppress the transcription of cancer-promoting genes...
July 5, 2017: Cold Spring Harbor Perspectives in Medicine
Jae-Seok Roe, Christopher R Vakoc
Acute myeloid leukemia (AML) is often initiated by genetic alterations of machineries that regulate chromatin and transcription, thereby blocking cell differentiation. Such mechanisms may also render leukemia cells vulnerable to perturbations of transcriptional regulators, which includes small molecules targeting the coactivator protein BRD4. Numerous studies have validated BRD4 as a therapeutic target in diverse subtypes of AML; however, the vital function of BRD4 in this disease is only beginning to be understood...
2016: Cold Spring Harbor Symposia on Quantitative Biology
Amanda R Oran, Clare M Adams, Xiao-Yong Zhang, Victoria J Gennaro, Harla K Pfeiffer, Hestia S Mellert, Hans E Seidel, Kirsten Mascioli, Jordan Kaplan, Mahmoud R Gaballa, Chen Shen, Isidore Rigoutsos, Michael P King, Justin L Cotney, Jamie J Arnold, Suresh D Sharma, Ubaldo E Martinez-Outschoorn, Christopher R Vakoc, Lewis A Chodosh, James E Thompson, James E Bradner, Craig E Cameron, Gerald S Shadel, Christine M Eischen, Steven B McMahon
Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production...
November 8, 2016: Oncotarget
Yu-Han Huang, Christopher R Vakoc
Identifying molecular biomarkers that predict cancer drug efficacy is crucial for the advancement of precision medicine. In this issue of Cell, Iorio et al. nominate hundreds of potential genetic and epigenetic biomarkers through high-throughput drug screening in ∼1,000 molecularly annotated cancer cell lines.
July 28, 2016: Cell
Tim D D Somerville, Christopher R Vakoc
In this issue of Cancer Cell, Lu et al. use a mouse model of DNMT3A(R882H)/NRAS(G12D) acute myeloid leukemia to define a cascade of chromatin changes that emanate from DNMT3A-bound enhancers to initiate disease. The authors also reveal a chemical strategy to interrupt this process.
July 11, 2016: Cancer Cell
Anja F Hohmann, Laetitia J Martin, Jessica L Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher R Vakoc
Here we show that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI-SNF chromatin-remodeling complex to sustain MYC transcription, rapid cell proliferation and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain that selectively suppress the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9 that retains functionality despite a radically altered bromodomain pocket...
September 2016: Nature Chemical Biology
Qiang Zhang, Lei Zeng, Chen Shen, Ying Ju, Tsuyoshi Konuma, Chengcheng Zhao, Christopher R Vakoc, Ming-Ming Zhou
The bromodomains and extra-terminal domain (BET) proteins direct gene transcription in chromatin, and represent new drug targets for cancer and inflammation. Here we report that the ET domain of the BET protein BRD4 recognizes an amphipathic protein sequence motif through establishing a two-strand antiparallel β sheet anchored on a hydrophobic cleft of the three-helix bundle. This structural mechanism likely explains BRD4 interactions with numerous cellular and viral proteins such as Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen, and NSD3 whose interaction with BRD4 via this ET domain mechanism is essential for acute myeloid leukemia maintenance...
July 6, 2016: Structure
Nilgun Tasdemir, Ana Banito, Jae-Seok Roe, Direna Alonso-Curbelo, Matthew Camiolo, Darjus F Tschaharganeh, Chun-Hao Huang, Ozlem Aksoy, Jessica E Bolden, Chi-Chao Chen, Myles Fennell, Vishal Thapar, Agustin Chicas, Christopher R Vakoc, Scott W Lowe
UNLABELLED: Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes...
June 2016: Cancer Discovery
Anand S Bhagwat, Jae-Seok Roe, Beverly Y L Mok, Anja F Hohmann, Junwei Shi, Christopher R Vakoc
The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis...
April 19, 2016: Cell Reports
Laetitia J Martin, Manfred Koegl, Gerd Bader, Xiao-Ling Cockcroft, Oleg Fedorov, Dennis Fiegen, Thomas Gerstberger, Marco H Hofmann, Anja F Hohmann, Dirk Kessler, Stefan Knapp, Petr Knesl, Stefan Kornigg, Susanne Müller, Herbert Nar, Catherine Rogers, Klaus Rumpel, Otmar Schaaf, Steffen Steurer, Cynthia Tallant, Christopher R Vakoc, Markus Zeeb, Andreas Zoephel, Mark Pearson, Guido Boehmelt, Darryl McConnell
Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF) complex are recurrently mutated in tumors, suggesting that altering the activity of the complex plays a role in oncogenesis. However, the role that the individual subunits play in this process is not clear. We set out to develop an inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its function within the SWI/SNF complex. Here, we present the discovery and development of a potent and selective BRD9 bromodomain inhibitor series based on a new pyridinone-like scaffold...
May 26, 2016: Journal of Medicinal Chemistry
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