Publications by authors named "Matthew Lawlor"

26 Publications

  • Page 1 of 1

Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19.

Nat Commun 2021 02 26;12(1):1325. Epub 2021 Feb 26.

NewYork-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA.

The coronavirus disease 2019 (COVID-19) can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections, but their benefit has not been assessed in COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1 through May 12, 2020 with study period ending on June 11, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline sociodemographic and clinical characteristics, and outpatient medications. The primary endpoint includes in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use is significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.47, 95% CI 0.36-0.62, p < 0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 is associated with lower inpatient mortality.
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http://dx.doi.org/10.1038/s41467-021-21553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910606PMC
February 2021

A Tumor Suppressor Enhancer of in T-cell development and leukemia.

Blood Cancer Discov 2021 Jan 24;2(1):92-109. Epub 2020 Nov 24.

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA.

Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the promoter in multiple hematopoietic populations, including T-cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced levels in T-ALL cells. Moreover, PE-null mice show reduced levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810363PMC
January 2021

Discordance in activated partial thromboplastin time and anti-factor Xa levels in COVID-19 patients on heparin therapy.

Thromb Res 2021 02 28;198:79-82. Epub 2020 Nov 28.

Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, 630 W 168th St, New York, NY 10032, United States oF America. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698679PMC
February 2021

Admission Cardiac Diagnostic Testing with Electrocardiography and Troponin Measurement Prognosticates Increased 30-Day Mortality in COVID-19.

J Am Heart Assoc 2021 01 10;10(1):e018476. Epub 2020 Nov 10.

Seymour, Paul, and Gloria Milstein Division of Cardiology Department of Medicine Columbia University Irving Medical Center New York NY.

Background Cardiovascular involvement in coronavirus disease 2019 (COVID-19) is common and leads to worsened mortality. Diagnostic cardiovascular studies may be helpful for resource appropriation and identifying patients at increased risk for death. Methods and Results We analyzed 887 patients (aged 64±17 years) admitted with COVID-19 from March 1 to April 3, 2020 in New York City with 12 lead electrocardiography within 2 days of diagnosis. Demographics, comorbidities, and laboratory testing, including high sensitivity cardiac troponin T (hs-cTnT), were abstracted. At 30 days follow-up, 556 patients (63%) were living without requiring mechanical ventilation, 123 (14%) were living and required mechanical ventilation, and 203 (23%) had expired. Electrocardiography findings included atrial fibrillation or atrial flutter (AF/AFL) in 46 (5%) and ST-T wave changes in 306 (38%). 27 (59%) patients with AF/AFL expired as compared to 181 (21%) of 841 with other non-life-threatening rhythms (<0.001). Multivariable analysis incorporating age, comorbidities, AF/AFL, QRS abnormalities, and ST-T wave changes, and initial hs-cTnT ≥20 ng/L showed that increased age (HR 1.04/year), elevated hs-cTnT (HR 4.57), AF/AFL (HR 2.07), and a history of coronary artery disease (HR 1.56) and active cancer (HR 1.87) were associated with increased mortality. Conclusions Myocardial injury with hs-cTnT ≥20 ng/L, in addition to cardiac conduction perturbations, especially AF/AFL, upon hospital admission for COVID-19 infection is associated with markedly increased risk for mortality than either diagnostic abnormality alone.
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http://dx.doi.org/10.1161/JAHA.120.018476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955502PMC
January 2021

The Prognostic Value of Electrocardiogram at Presentation to Emergency Department in Patients With COVID-19.

Mayo Clin Proc 2020 10 15;95(10):2099-2109. Epub 2020 Aug 15.

Seymour, Paul, and Gloria Milstein Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY; Department of Medicine, Columbia University Irving Medical Center, New York, NY; Division of Cardiology, Department of Medicine, Weill Cornell University Medical Center, New York, NY. Electronic address:

Objective: To study whether combining vital signs and electrocardiogram (ECG) analysis can improve early prognostication.

Methods: This study analyzed 1258 adults with coronavirus disease 2019 who were seen at three hospitals in New York in March and April 2020. Electrocardiograms at presentation to the emergency department were systematically read by electrophysiologists. The primary outcome was a composite of mechanical ventilation or death 48 hours from diagnosis. The prognostic value of ECG abnormalities was assessed in a model adjusted for demographics, comorbidities, and vital signs.

Results: At 48 hours, 73 of 1258 patients (5.8%) had died and 174 of 1258 (13.8%) were alive but receiving mechanical ventilation with 277 of 1258 (22.0%) patients dying by 30 days. Early development of respiratory failure was common, with 53% of all intubations occurring within 48 hours of presentation. In a multivariable logistic regression, atrial fibrillation/flutter (odds ratio [OR], 2.5; 95% CI, 1.1 to 6.2), right ventricular strain (OR, 2.7; 95% CI, 1.3 to 6.1), and ST segment abnormalities (OR, 2.4; 95% CI, 1.5 to 3.8) were associated with death or mechanical ventilation at 48 hours. In 108 patients without these ECG abnormalities and with normal respiratory vitals (rate <20 breaths/min and saturation >95%), only 5 (4.6%) died or required mechanical ventilation by 48 hours versus 68 of 216 patients (31.5%) having both ECG and respiratory vital sign abnormalities.

Conclusion: The combination of abnormal respiratory vital signs and ECG findings of atrial fibrillation/flutter, right ventricular strain, or ST segment abnormalities accurately prognosticates early deterioration in patients with coronavirus disease 2019 and may assist with patient triage.
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http://dx.doi.org/10.1016/j.mayocp.2020.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428764PMC
October 2020

Association Between Antecedent Statin Use and Decreased Mortality in Hospitalized Patients with COVID-19.

Res Sq 2020 Aug 11. Epub 2020 Aug 11.

NewYork-Presbyterian Hospital and the Columbia University Irving Medical Center; Cardiovascular Research Foundation.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections and ARDS, but their benefit has not been assessed in COVID-19. Thus, we sought to determine whether antecedent statin use is associated with lower in-hospital mortality in patients hospitalized for COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1 through May 12 , 2020 with study period ending on June 11 , 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline socio-demographic and clinical characteristics, and outpatient medications. The primary endpoint included in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, demographic, baseline, and outpatient medication information were well balanced. Statin use was significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.48, 95% CI 0.36 â€" 0.64, p<0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 was associated with lower inpatient mortality. Randomized clinical trials evaluating the utility of statin therapy in patients with COVID-19 are needed.
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http://dx.doi.org/10.21203/rs.3.rs-56210/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430584PMC
August 2020

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Authors:
Lauren A Eberly Aaron Richterman Anne G Beckett Bram Wispelwey Regan H Marsh Emily C Cleveland Manchanda Cindy Y Chang Robert J Glynn Katherine C Brooks Robert Boxer Rose Kakoza Jennifer Goldsmith Joseph Loscalzo Michelle Morse Eldrin F Lewis Samantha Abel Ayrenne Adams Joseph Anaya Erik H Andrews Benjamin Atkinson Viswatej Avutu Alexandra Bachorik Omar Badri Mariel Bailey Katie Baird Salina Bakshi Denis Balaban Kenneth Barshop Emily Baumrin Omar Bayomy Julia Beamesderfer Nora Becker David D Berg Adam N Berman Steven M Blum Alexander P Boardman Kaeleen Boden Robert A Bonacci Sarah Brown Kirsti Campbell Siobhan Case Emily Cetrone Alexandra Charrow David Chiang Devin Clark Aaron J Cohen Alissa Cooper Tomas Cordova C Nicholas Cuneo Alsina Alejandro de Feria Karen Deffenbacher Ersilia M DeFilippis Geneva DeGregorio Aaron J Deutsch Bradford Diephuis Sanjay Divakaran Peter Dorschner Nicholas Downing Caitlin Drescher Kristin M D'Silva Peter Dunbar David Duong Sarah Earp Christine Eckhardt Scott A Elman Ross England Kay Everett Natalie Fedotova Tamara Feingold-Link Mark Ferreira Herrick Fisher Patricia Foo Michael Foote Idalid Franco Thomas Gilliland Jacqueline Greb Katherine Greco Sungat Grewal Benjamin Grin Matthew E Growdon Brendan Guercio Cynthia K Hahn Brian Hasselfeld Erika J Haydu Zachary Hermes Gordon Hildick-Smith Zachary Holcomb Kathryn Holroyd Laura Horton George Huang Stanley Jablonski Douglas Jacobs Nina Jain Sohan Japa Richard Joseph Mariya Kalashnikova Neil Kalwani Daniel Kang Abraar Karan Joel T Katz Daniel Kellner Khameer Kidia June-Ho Kim Scott M Knowles Laura Kolbe Idil Kore Yiannis Koullias Ifedayo Kuye Joshua Lang Matthew Lawlor Melissa G Lechner Ken Lee Scott Lee Zachary Lee Neha Limaye Stephanie Lin-Beckford Marla Lipsyc Jessica Little Julia Loewenthal Ranjani Logaraj Diana M Lopez Daniel Loriaux Yi Lu Kevin Ma Nareh Marukian Wilfredo Matias Jared R Mayers Ian McConnell Michael McLaughlin Christina Meade Catherine Meador Anish Mehta Elizabeth Messenger Constantinos Michaelidis Jacob Mirsky Emilie Mitten Alisa Mueller Jyotsna Mullur Amir Munir Emily Murphy Ellen Nagami Abirami Natarajan Michelle Nsahlai Chijioke Nze Noreen Okwara Peter Olds Rafael Paez Michael Pardo Siddharth Patel Alec Petersen Laura Phelan Erica Pimenta Daniel Pipilas Molly Plovanich Denise Pong Brian W Powers Anita Rao Haiyan Ramirez Batlle Mattheus Ramsis Anna Reichardt Sheridan Reiger Michelle Rengarajan Stephanie Rico Benjamin N Rome Rachael Rosales Lisa Rotenstein Alexis Roy Sarah Royston Hallie Rozansky Meghan Rudder Christine E Ryan Sanjay Salgado Pablo Sanchez Jennifer Schulte Aswin Sekar Nicholas Semenkovich Evan Shannon Neil Shaw Andrew Ben Shorten William Shrauner Lauren Sinnenberg James W Smithy Gregory Snyder Anirudh Sreekrishnan Hans Stabenau Eleni Stavrou Andrew Stergachis Robert Stern Alexander Stone Shervin Tabrizi Sam Tanyos Cristina Thomas Haley Thun Kristine Torres-Lockhart An Tran Carolyn Treasure Frederick D Tsai Stephen Tsaur Evan Tschirhart Justin Tuwatananurak Ramkumar V Venkateswaran Anastasia Vishnevetsky Lindsay Wahl April Wall Frances Wallace Elisa Walsh Priscilla Wang Heather B Ward Lindsay N Warner Lachelle D Weeks Kipp Weiskopf Jordan Wengrod Jessica N Williams Marisa Winkler Jeffrey L Wong Devin Worster Aileen Wright Caroline Wunsch Jamila S Wynter Chase Yarbrough Wai-Ying Yau Daniel Yazdi Jennifer Yeh Maria A Yialamas Nicholas Yozamp Marina Zambrotta Rebecca Zon

Circ Heart Fail 2019 11 29;12(11):e006214. Epub 2019 Oct 29.

Division of Cardiovascular Medicine, and Department of Medicine (E.F..L.), Brigham and Women's Hospital, Boston, MA.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality.

Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.

Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183732PMC
November 2019

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.

Cancer Cell 2019 10 19;36(4):369-384.e13. Epub 2019 Sep 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address:

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
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http://dx.doi.org/10.1016/j.ccell.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801112PMC
October 2019

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.

Cancer Cell 2019 05;35(5):752-766.e9

Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address:

Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.
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http://dx.doi.org/10.1016/j.ccell.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945775PMC
May 2019

Small-molecule targeting of brachyury transcription factor addiction in chordoma.

Nat Med 2019 02 21;25(2):292-300. Epub 2019 Jan 21.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Chordoma is a primary bone cancer with no approved therapy. The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors. In chordoma, we find that T is associated with a 1.5-Mb region containing 'super-enhancers' and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
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http://dx.doi.org/10.1038/s41591-018-0312-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633917PMC
February 2019

Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition.

Cancer Res 2019 03 10;79(5):994-1009. Epub 2019 Jan 10.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist. In this study, we identify regulatory regions of the enhancer essential for gene expression and GIST cell viability. Given the dependence of GIST upon enhancer-driven expression of RTKs, we hypothesized that the enhancer domains could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell-cycle arrest, apoptosis, and cell death, with unique sensitivity in GIST cells arising from attenuation of the enhancer domain and reduced gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to superior cytotoxic effects and , with BBI preventing tumor growth in TKI-resistant xenografts. Resistance to select BBI in GIST was attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST. SIGNIFICANCE: Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397693PMC
March 2019

Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma.

Cell Rep 2018 12;25(13):3693-3705.e6

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; VA Boston Healthcare System, Boston, MA, USA. Electronic address:

The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.
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http://dx.doi.org/10.1016/j.celrep.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407615PMC
December 2018

Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia.

Cancer Cell 2018 12 29;34(6):982-995.e7. Epub 2018 Nov 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address:

Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival. Targeting enhancer signaling via BET bromodomain inhibition disrupts super enhancer-dependent gene expression with selective effects on CLL core regulatory circuitry, conferring potent anti-tumor activity.
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http://dx.doi.org/10.1016/j.ccell.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298230PMC
December 2018

Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome.

Proc Natl Acad Sci U S A 2018 06 4;115(25):E5746-E5755. Epub 2018 Jun 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;

Activating mutations in the KIT or PDGFRA receptor tyrosine kinases are hallmarks of gastrointestinal stromal tumor (GIST). The biological underpinnings of recurrence following resection or disease progression beyond kinase mutation are poorly understood. Utilizing chromatin immunoprecipitation with sequencing of tumor samples and cell lines, we describe the enhancer landscape of GIST, highlighting genes that reinforce and extend our understanding of these neoplasms. A group of core transcription factors can be distinguished from others unique to localized and metastatic disease. The transcription factor HAND1 emerges in metastatic disease, binds to established GIST-associated enhancers, and facilitates GIST cell proliferation and KIT gene expression. The pattern of transcription factor expression in primary tumors is predictive of metastasis-free survival in GIST patients. These results provide insight into the enhancer landscape and transcription factor network underlying GIST, and define a unique strategy for predicting clinical behavior of this disease.
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http://dx.doi.org/10.1073/pnas.1802079115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016782PMC
June 2018

The dTAG system for immediate and target-specific protein degradation.

Nat Chem Biol 2018 05 26;14(5):431-441. Epub 2018 Mar 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12 with expression of FKBP12 in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
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http://dx.doi.org/10.1038/s41589-018-0021-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295913PMC
May 2018

Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands.

Nat Chem Biol 2018 04 5;14(4):405-412. Epub 2018 Mar 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.
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http://dx.doi.org/10.1038/s41589-018-0010-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866761PMC
April 2018

YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis.

Cancer Res 2018 05 28;78(10):2705-2720. Epub 2018 Feb 28.

Abramson Family Cancer Research Institute, Department of Pathology & Laboratory Medicine, Penn Sarcoma Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment. A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-4052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314302PMC
May 2018

Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma.

Nat Genet 2018 04 29;50(4):515-523. Epub 2018 Jan 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy. These highly occupied MYCN target genes show tissue-specific expression and are linked to poor patient survival. The activity of genes with MYCN-occupied enhancers is dependent on the tissue-specific transcription factor TWIST1, which co-occupies enhancers with MYCN and is required for MYCN-dependent proliferation. These data implicate tissue-specific enhancers in defining often highly tumor-specific 'MYC target gene signatures' and identify disruption of the MYCN enhancer regulatory axis as a promising therapeutic strategy in neuroblastoma.
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http://dx.doi.org/10.1038/s41588-018-0044-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310397PMC
April 2018

Synthetic transcription elongation factors license transcription across repressive chromatin.

Science 2017 12 30;358(6370):1617-1622. Epub 2017 Nov 30.

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy. The modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci.
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http://dx.doi.org/10.1126/science.aan6414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037176PMC
December 2017

The Rivas Cohort Study: design and baseline characteristics of a Nicaraguan cohort.

BMC Nephrol 2016 07 25;17:93. Epub 2016 Jul 25.

Boston University Schools of Medicine and Public Health, 72 E. Concord Street, Boston, MA, 02118, USA.

Background: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non-representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated.

Methods: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created.

Results: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow-up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits.

Conclusion: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long-term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies.
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http://dx.doi.org/10.1186/s12882-016-0320-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959050PMC
July 2016

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer.

Cancer Discov 2016 09 16;6(9):1006-21. Epub 2016 Jun 16.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Unlabelled: As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a potent open-source EZH2 inhibitor, JQEZ5, that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer.

Significance: EZH2 overexpression induces murine lung cancers that are similar to human NSCLC with high EZH2 expression and low levels of phosphorylated AKT and ERK, implicating biomarkers for EZH2 inhibitor sensitivity. Our EZH2 inhibitor, JQEZ5, promotes regression of these tumors, revealing a potential role for anti-EZH2 therapy in lung cancer. Cancer Discov; 6(9); 1006-21. ©2016 AACR.See related commentary by Frankel et al., p. 949This article is highlighted in the In This Issue feature, p. 932.
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http://dx.doi.org/10.1158/2159-8290.CD-16-0164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010480PMC
September 2016

Boundaries, shading, and border ownership: A cusp at their interaction.

J Physiol Paris 2009 Jan-Mar;103(1-2):18-36. Epub 2009 May 27.

Yale University, New Haven, CT 06520-8285, United States.

The association of borders with "figure" rather than "background" provides a topological organizing principle for early vision. Such global influences have recently been shown to have local effects, with neuronal activity modulated by stimulus properties from well outside the classical receptive field. We extend the theoretical analysis of such phenomena by developing the geometry of interaction between shading, boundaries, and boundary ownership for smooth surfaces. The purely exterior edges of smooth objects enjoy a fold-type relationship between shading and boundary, due to foreshortening, while the background is cut off transversely. However, at cusp points in the image mapping the exterior boundary ends abruptly. Since such singular points are notoriously unstable, we conjecture that this process is regularized by a natural quantization of suggestive contours due to physiological boundary-detection mechanisms. The result extends a theorem about how contours must end to one that characterizes surface (Gaussian) curvature in the neighborhood of where they appear to end. Apparent contours and their interaction with local shading thus provide important monocular shape cues.
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http://dx.doi.org/10.1016/j.jphysparis.2009.05.005DOI Listing
December 2009

Yersiniabactin is a virulence factor for Klebsiella pneumoniae during pulmonary infection.

Infect Immun 2007 Mar 12;75(3):1463-72. Epub 2007 Jan 12.

Department of Molecular Microbiology, Campus Box 8230, 660 S. Euclid Ave., St. Louis, MO 63110, USA.

Iron acquisition systems are essential for the in vivo growth of bacterial pathogens. Despite the epidemiological importance of Klebsiella pneumoniae, few experiments have examined the importance of siderophores in the pathogenesis of this species. A previously reported signature-tagged mutagenesis screen identified an attenuated strain that featured an insertional disruption in ybtQ, which encodes a transporter for the siderophore yersiniabactin. We used this finding as a starting point to evaluate the importance of siderophores in the physiology and pathogenesis of K. pneumoniae. Isogenic strains carrying in-frame deletions in genes required for the synthesis of either enterobactin or yersiniabactin were constructed, and the growth of these mutants was examined both in vitro and in vivo using an intranasal infection model. The results suggest divergent functions for each siderophore in different environments, with enterobactin being more important for growth in vitro under iron limitation than in vivo and the reverse being true for the yersiniabactin locus. These observations represent the first examination of isogenic mutants in iron acquisition systems for K. pneumoniae and may indicate that the acquisition of nonenterobactin siderophores is an important step in the evolution of virulent enterobacterial strains.
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http://dx.doi.org/10.1128/IAI.00372-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828572PMC
March 2007

Comparison of the host responses to wild-type and cpsB mutant Klebsiella pneumoniae infections.

Infect Immun 2006 Sep;74(9):5402-7

Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.

Previously, we established an intranasal mouse model of Klebsiella pneumoniae infection and validated its utility using a highly virulent wild-type strain and an avirulent capsular polysaccharide mutant. In the present study we compare the host responses to both infections by examining cytokine production, cellular infiltration, pulmonary histology, and intranasal immunization.
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http://dx.doi.org/10.1128/IAI.00244-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594822PMC
September 2006

Identification of Klebsiella pneumoniae virulence determinants using an intranasal infection model.

Mol Microbiol 2005 Nov;58(4):1054-73

Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110, USA.

Klebsiella pneumoniae is a Gram-negative enterobacterium that has historically been, and currently remains, a significant cause of human disease. It is a frequent cause of urinary tract infections and pneumonia, and subsequent systemic infections can have mortality rates as high as 60%. Despite its clinical significance, few virulence factors of K. pneumoniae have been identified or characterized. In this study we present a mouse model of acute K. pneumoniae respiratory infection using an intranasal inoculation method, and examine the progression of both pulmonary and systemic disease. Wild-type infection recapitulates many aspects of clinical disease, including significant bacterial growth in both the trachea and lungs, an inflammatory immune response characterized by dramatic neutrophil influx, and a steady progression to systemic disease with ensuing mortality. These observations are contrasted with an infection by an isogenic capsule-deficient strain that shows an inability to cause disease in either pulmonary or systemic tissues. The consistency and clinical accuracy of the intranasal mouse model proved to be a useful tool as we conducted a genetic screen to identify novel virulence factors of K. pneumoniae. A total of 4800 independent insertional mutants were evaluated using a signature-tagged mutagenesis protocol. A total of 106 independent mutants failed to be recovered from either the lungs or spleens of infected mice. Small scale independent infections proved to be helpful as a secondary screening method, as opposed to the more traditional competitive index assay. Those mutants showing verified attenuation contained insertions in loci with a variety of putative functions, including a large number of hypothetical open reading frames. Subsequent experiments support the premise that the central mechanism of K. pneumoniae pathogenesis is the production of a polysaccharide-rich cell surface that provides protection from the inflammatory response.
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http://dx.doi.org/10.1111/j.1365-2958.2005.04918.xDOI Listing
November 2005