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Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins. Mol Cancer Ther; 13(6); 1492–502. ©2014 AACR.

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PDF file - 1496K, Figure S1 - control expression and SMM hits representation; luciferase assay with MITF for BRD32048 and luciferase assay using BRD32048 analogs. Figure S2 - SPR data control graphs for TBX21 reference experiment. Figure S3 alternative SPR data for antibody reference; RU signals for additional reference surfaces. Figure S4 - ETV1 silencing validation data at mRNA and protein levels; alternative view of LNCaP signatures overlap; the proliferative effects of BRD32048 in LNCaP cell line and QPCR validation of BRD32048 inhibited targets. Figure S5 - control expression of indicated proteins and control invasion assays; - proliferation of cell lines in the presence of BRD32048. Figure S6 supportive mechanistic evidence such as ETV1-DNA interaction; BRD32048-induced loss of endogenous ETV1 and the effect of BRD32048 on an acetylation-deficient ETV1 mutant.

Background and ObjectivesFacioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease characterized by progressive muscle weakness. MRI is a sensitive assessment of disease severity and progression. We developed a quantitative whole-body (WB) musculoskeletal MRI (WB-MSK-MRI) protocol analyzing muscles in their entirety. This study aimed to assess WB-MSK-MRI as a potential imaging biomarker providing reliable measurements of muscle health that capture disease heterogeneity and clinically meaningful composite assessments correlating with severity and more responsive to change in clinical trials.MethodsParticipants aged 18–65 years, with genetically confirmed FSHD1, clinical severity 2 to 4 (Ricci scale, range 0–5), and ≥1 short tau inversion recovery–positive lower extremity muscle eligible for needle biopsy, enrolled at 6 sites and were imaged twice 4–12 weeks apart. Volumetric analysis of muscle fat infiltration (MFI), muscle fat fraction (MFF), and lean muscle volume (LMV) in 18 (36 total) muscles from bilateral shoulder, proximal arm, trunk, and legs was performed after automated atlas-based segmentation, followed by manual verification. A WB composite score, including muscles at highest risk for progression, and functional cross-sectional composites for correlation with relevant functional outcomes including timed up and go (TUG), FSHD-TUG, and reachable workspace (RWS), were developed.ResultsSeventeen participants enrolled in this study; 16 follow-up MRIs were performed at 52 days (range 36–85 days). Functional cross-sectional composites (MFF and MFI) showed moderate to strong correlations: TUG (ρ = 0.71, ρ = 0.83), FSHD-TUG (ρ = 0.73, ρ = 0.73), and RWS (left arm: ρ = −0.71, ρ = −0.53; right arm: ρ = −0.61, ρ = −0.65). WB composite variability: LMVtot, coefficient of variation (CV) 1.9% and 3.4%; MFFtot, within-subject SD (Sw) 0.5% and 1.5%; and MFItot (Sw), 0.3% and 0.4% for normal and intermediate muscles, respectively. CV and Sw were higher in intermediate (MFI ≥0.10; MFF DiscussionWe developed a WB-MSK-MRI protocol and composite measures that capture disease heterogeneity and assess muscle involvement as it correlates with FSHD-relevant clinical endpoints. Functional composites robustly correlate with functional assessments. Stability of the WB composite shows that it could be an assessment of change in therapeutic clinical trials.Classification of EvidenceThis study provides Class II evidence that quantitative WB-MSK-MRI findings associate with FSHD1 severity measured using established functional assessments.

Item does not contain fulltext INTRODUCTION/AIMS: Functional performance tests are the gold standard to assess disease progression and treatment effects in neuromuscular disorders. These tests can be confounded by motivation, pain, fatigue, and learning effects, increasing variability and decreasing sensitivity to disease progression, limiting efficacy assessment in clinical trials with small sample sizes. We aimed to develop and validate a quantitative and objective method to measure skeletal muscle volume and fat content based on whole-body fat-referenced magnetic resonance imaging (MRI) for use in multisite clinical trials. METHODS: Subjects aged 18 to 65 years, genetically confirmed facioscapulohumeral muscular dystrophy 1 (FSHD1), clinical severity 2 to 4 (Ricci's scale, range 0-5), were enrolled at six sites and imaged twice 4-12 weeks apart with T1-weighted two-point Dixon MRI covering the torso and upper and lower extremities. Thirty-six muscles were volumetrically segmented using semi-automatic multi-atlas-based segmentation. Muscle fat fraction (MFF), muscle fat infiltration (MFI), and lean muscle volume (LMV) were quantified for each muscle using fat-referenced quantification. RESULTS: Seventeen patients (mean age ± SD, 49.4 years ±13.02; 12 men) were enrolled. Within-patient SD ranged from 1.00% to 3.51% for MFF and 0.40% to 1.48% for MFI in individual muscles. For LMV, coefficients of variation ranged from 2.7% to 11.7%. For the composite score average of all muscles, observed SDs were 0.70% and 0.32% for MFF and MFI, respectively; composite LMV coefficient of variation was 2.0%. DISCUSSION: We developed and validated a method for measuring skeletal muscle volume and fat content for use in multisite clinical trials of neuromuscular disorders.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4 locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause. SIGNIFICANCE STATEMENT: Using patient-derived facioscapulohumeral muscular dystrophy (FSHD) myotubes, we characterize the pharmacological relationships between p38α/β inhibition, double homeobox 4 (DUX4) expression, its downstream transcriptional program, and muscle cell death. p38α/β inhibition results in potent and specific DUX4 downregulation across multiple genotypes without significant effects in the process of myogenesis in vitro. These findings highlight the potential of p38α/β inhibitors for the treatment of FSHD, a condition that today has no approved therapies.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described, however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

Aims Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD). Methods This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood. Results PK profiles were similar between healthy volunteers and FSHD subjects, with mean Cmax and AUC0-12 for 15 mg in FSHD subjects (Part B) of 85.0 ± 16.7 ng*h/mL and 410 ± 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 ± 10.5 ng/g [7.5 mg] to 97.2 ± 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from ~0.67 to ~1 at estimated tmax of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited. Conclusion Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. Clinical trial registration Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the

Sickle cell disease (SCD) results from genetic mutation in the β-globin gene encoding a subunit of the adult form of hemoglobin (HbA), leading to red blood cell (RBC) deformation and disease pathology. It has been demonstrated that reactivation of the fetal ortholog of the hemoglobin beta subunit, HBγ (also referred to as HBG proteins), can prevent or reduce disease-related pathophysiology. In SCD, the presence of HBG protein in hemoglobin tetramers prevents sickle hemoglobin polymerization under deoxygenated conditions and therefore may be of therapeutic benefit in SCD. FTX 6058, a novel orally bioavailable small molecule, is in development for the treatment of sickle cell disease (SCD) by Fulcrum Therapeutics. FTX-6058 was demonstrated to inhibit the novel biological target and elevate the expression of HBγ, resulting in induction of fetal hemoglobin (HbF) tetramer in differentiated human primary CD34+ cells. The in vivo target engagement (TE) and pharmacologic effects of FTX-6058 were characterized in wild-type CD-1 mice and humanized Townes SCD mice, with TE also confirmed in non-human primates. In CD-1 mice, once-daily (QD) FTX-6058 oral administration induced TE in a time- and dose-dependent manner and most markedly in erythroid lineage (Ter119+) cells derived from bone marrow, the putative therapeutic compartment, and increased transcript levels of Hbb-bh1, a murine embryonic hemoglobin surrogate for human HBG gene. Steady state TE in circulating monocytes, following repeated QD FTX-6058 administration, correlated well with that in bone marrow-derived erythroid cells, suggesting peripheral monocytes as a suitable surrogate for assessing erythroid TE activity in Fulcrum's Phase 1 study. In non-human primate cynomolgus monkeys, QD oral dosing of FTX-6058 as early as for 7 days induced robust and comparable TE in bone marrow derived CD34+ erythroid progenitors and circulating monocytes, further supporting the use of monocytes to assess TE in bone marrow. Mouse data also provided evidence of the reversibility of TE effects once dosing is stopped. In repeat-dose studies in the humanized Townes SCD mouse model, FTX-6058 was superior to standard of care hydroxyurea as measured by human HBG1 transgene induction and increased %F-cells and HBG1 protein levels. Furthermore, the induction of %F cells was sustainable for several days after dosing cessation. These in vivo studies have demonstrated that FTX-6058 engages its novel biological target in multiple preclinical models and induces HbF expression at plasma concentrations likely to b e readily achievable in clinic, and peripheral monocytes is a suitable surrogate for assessing TE in bone marrow erythroid cells, which could be beneficial to patients with SCD. Disclosures Xie: Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Silver:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

FSHD is caused by the loss of repression at the D4Z4 locus leading to DUX4 expression in skeletal muscle, activation of its early embryonic transcriptional program and muscle fiber death. While progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.VISUAL ABSTRACT

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Mucin-1 kidney disease, previously described as medullary cystic kidney disease type 1 (MCKD1, OMIM 174000), is an autosomal dominant tubulointerstitial kidney disease recently shown to be caused by a single-base insertion within the variable number tandem repeat region of the MUC1 gene. Because of variable age of disease onset and often subtle signs and symptoms, clinical diagnosis of mucin-1 kidney disease and differentiation from other forms of hereditary kidney disease have been difficult. The causal insertion resides in a variable number tandem repeat region with high GC content, which has made detection by standard next-generation sequencing impossible to date. The inherently difficult nature of this mutation required an alternative method for routine detection and clinical diagnosis of the disease. We therefore developed and validated a mass spectrometry–based probe extension assay with a series of internal controls to detect the insertion event using 24 previously characterized positive samples from patients with mucin-1 kidney disease and 24 control samples known to be wild type for the variant. Validation results indicate an accurate and reliable test for clinically establishing the molecular diagnosis of mucin-1 kidney disease with 100% sensitivity and specificity across 275 tests called., Carlos Slim Foundation. Slim Initiative for Genomic Medicine

Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

We have discovered a novel class of heterocyclic sulfonamides that act as antagonists of the S1P1 receptor. While members of this series identified from a high-throughput screen showed promising levels of potency in a cell-based assay measuring the inhibition of receptor internalization, most compounds were excessively lipophilic and contained an oxidation-prone thioether moiety. As a result, such compounds suffered from poor physical properties and metabolic stability, limiting their utility as in vivo probes. By removing the thioether group and systematically developing an understanding of structure–activity relationships and the effects of lipophilicity on potency within this series, we have been able to identify potent compounds with vastly improved physical properties. A representative enantiopure triazole sulfonamide (33) has measurable bioavailability following a low (3 mg/kg) oral dose in rat, highlighting an achievement of the early hit-to-lead efforts for this series.

SUMMARYWe previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.HIGHLIGHTSA new gene expression profiling method, L1000, dramatically lowers costThe Connectivity Map database now includes 1.3 million publicly accessible L1000 perturbational profilesThis expanded Connectivity Map facilitates discovery of small molecule mechanism of action and functional annotation of genetic variantsThe work establishes feasibility and utility of a truly comprehensive Connectivity Map

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMapcan be used to discover mechanism of action of small molecules, functionally annotate genetic variants ofdisease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

Prostate cancer remains one of the leading causes of cancer-related death in men. Chromosomal rearrangements resulting in the fusion of the androgen regulated gene TMPRSS2 and the ETS-family transcription factor ERG occur in over 50% of all prostate cancer cases. Recent studies enabled by genome-wide methodologies have implicated altered epigenomic landscapes and changes in DNA accessibility as major contributors to ERG-driven oncogenesis, however the precise mechanism underlying the ERG transcriptional signature has to date remained unclear. Here we performed the first endogenous purification and SILAC-mass spectrometric analysis of ERG in TMPRSS2-ERG prostate cancer cells. Remarkably, we demonstrate that ERG directly interacts with the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which was recently shown to be mutated in >20% of human malignancies. ERG co-localizes with BAF complexes genome-wide, resulting in specific ERG-dependent BAF complex targeting to sites enriched in known ERG, FOXA1, and HOXB13 motifs; additionally, loss of ERG in TMPRSS2-ERG driven cell lines results in dramatic retargeting of BAF complexes away from ERG-dependent sites, to sites enriched in known AR and CTCF motifs. Importantly, ERG-driven BAF complex retargeting contributes to activation of TMPRSS2-ERG prostate cancer gene expression signatures. We map the ERG-BAF interaction to a specific region within the ERG amino acid sequence and find that this region is required to bind BAF complexes. These studies reveal a novel, unexpected mechanism of action of ERG-driven oncogenesis and offers new strategies for therapeutic intervention. Citation Format: Gabriel J. Sandoval, John L. Pulice, David Y. Takeda, Monica A. Schenone, Marius Pop, Gaylor Boulay, Miguel N. Rivera, Lucienne Ronco, William C. Hahn, Cigall Kadoch. TMPRSS2-ERG drives global mistargeting of mammalian SWI/SNF (BAF) complexes in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 882.