32 Result(s)
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Christopher R. Vakoc
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Article
Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma
The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are...
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Article
Open AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the mast...
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Open AccessTargeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1
Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually r...
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Article
ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation
The EWS-FLI1 fusion oncoprotein deregulates transcription to initiate the paediatric cancer Ewing sarcoma. Here we used a domain-focused CRISPR screen to implicate the transcriptional repressor ETV6 as a uniqu...
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BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network
Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)—the most common ...
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Article
Open AccessSirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD+-dependent deacetylases and has established ...
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Article
OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage
Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft-cell-like human tumours2,3, particularly as...
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Article
Open AccessComparative optimization of combinatorial CRISPR screens
Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance of different function...
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Article
SMARCA4 biology in alveolar rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosi...
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Article
Open AccessBAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric tran...
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Open AccessACE: a probabilistic model for characterizing gene-level essentiality in CRISPR screens
High-throughput CRISPR-Cas9 knockout screens are widely used to evaluate gene essentiality in cancer research. Here we introduce a probabilistic modeling framework, Analysis of CRISPR-based Essentiality (ACE),...
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Article
Open AccessSuperior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells
There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic k...
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Article
A pliable ERα cistrome evades therapy
The transcription factor oestrogen receptor alpha (ERα) has long been targeted for therapeutic benefit in cancer, but drug resistance can emerge through a multitude of mechanisms. A study now reveals how the E...
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Article
Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma
Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here...
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Open AccessAuthor Correction: Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Article
Open AccessLineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection
Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and trans...
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Article
Open AccessSMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines
SMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screenin...
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Article
Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3
Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 ...
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Article
Author Correction: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Article
Open AccessTargeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single...
