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Articles by Benjamin Ebert
DCAF11-dependent molecular glue degrader activated by glutathionylation
Abstract Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18.
Stromal and endothelial transcriptional changes during progression from MGUS to myeloma and after treatment response
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Abstract Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is accompanied by profound remodeling of the bone marrow microenvironment (BME), yet the contribution of its non-immune compartment remains unclear. Using single-cell RNA sequencing in genetically engineered mouse models that recapitulate disease evolution, we transcriptionally profile endothelial cells (EC) and mesenchymal stem cells (MSC).
By Itziar Cenzano, Miguel Cocera, Marta J. Larrayoz, Lorea Campos-Dopazo, Sonia Sanz Verified, Azari Bantan, Amaia Vilas-Zornoza, Diego Alignani, Ignacio González, Javier Ruiz, Purificacion Ripalda-Cemborain, Emma Muiños-López, Vincenzo Lagani, Jesper Tegnér, Mikel Hernaez, Xabier Agirre, Benjamin Ebert, Bruno Paiva, Paula Rodríguez-Otero, Luis-Esteban Tamariz-Amador, Jesus San-Miguel, Jesús F San-Miguel, Borja Saez, Isabel A. Calvo, David Gomez-Cabrero, Felipe Prosper, Patxi San-Martin, Paula Aguirre-Ruiz, Aitziber Lopez, Marta Abengozar-Muela, José A. Martinez-Climent
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Nature
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Author Correction: The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis
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Correction to: Nature https://doi.org/10.1038/s41586-021-03341-5 Published online 17 March 2021 In the version of this article initially published, due to mistakes during file revision and figure assembly, there was a duplication error in Extended Data Fig. 10l, where the top-right 20% Control IL-1β image was a repeat of the lower-left 20% Jak2VF IgG image. In the initial submission, where current Extended Data Fig. 10l was originally presented as Fig.
By Trevor P. Fidler, Chenyi Xue, Mustafa Yalcinkaya, Brian D. Hardaway, Tong Xiao, Wenli Liu, David Thomas, Joachim Pircher, Carlos Silvestre-Roig, Andriana G. Kotini, Larry L. Luchsinger, Ying Wei, Marit Westerterp, Hans-Willem Snoeck, Eirini P. Papapetrou, Christian Schulz, Steffen Massberg, Oliver Soehnlein, Benjamin Ebert, Ross Levine, Muredach P. Reilly, Peter Libby, Nan Wang, Alan R. Tall, Sandra Abramowicz, Mohammad Ali Hajebrahimi
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Nature
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Charged molecular glue discovery enabled by targeted degron display
Abstract Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs).
Human plasma proteomic profile of clonal hematopoiesis - Nature Communications
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Abstract Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD).
By Zhi Yu, Amélie Vromman, Art Schuermans, Tetsushi Nakao, Mesbah Uddin, Abhishek Niroula, Gabriel K. Griffin, Michael C. Honigberg, Christopher Gibson, Daniel Katz, Usman Tahir, Jacqueline S. Dron, Michael Pan, Shriienidhie Ganesh, Joshua Weinstock, Ramachandran S. Vasan, Gina M. Peloso, Peter Ganz, JoAnn E. Manson, Joann Manson, Bernhard Haring, Charles Kooperberg, Joshua C. Bis, Bruce M. Psaty, Yuan-I Min, Adolfo Correa, Jerome I. Rotter, Stephen S. Rich, Benjamin Ebert, Bing Yu, Christie M. Ballantyne, Josef Coresh, Vijay Sankaran, Alexander Bick, Siddhartha Jaiswal, Robert Gerszten, NHLBI Trans-Omics, Peter Libby, Rajat Gupta
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Nature
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Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation
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Keywords zinc finger proteins ZF cereblon CRBN glutarimide analogs targeted protein degradation molecular glue degron specificity CRL4(CRBN) E3 ligase functional genomics flow-based sorting screens Introduction Molecular glue degraders modulate protein interfaces, enabling degradation of proteins lacking canonical binding sites, including transcription factors.1,2,3 These small molecules recruit a neosubstrate to an E3 ubiquitin ligase, leading to ubiquitylation and proteasomal...
By Mikołaj Słabicki, Jiho Park, Radosław Nowak, Jesse Pellman, Charles Zou, Hlib Razumkov, Jeannie Carreiro, Simran Rastogi, Anna P. Goldstein, Marek M. Nagiec, Katherine A. Donovan, Jianwei Che, Moritz Hunkeler, Qixiang Geng, Chi-Lin Hsu, Megha Lakshminarayan, Chelsea Shu, Rebecca L. Zon, Zuzanna Kozicka, Paul Park, Jonathan M. Tsai, Hojong Yoon, Lyn H. Jones, Adam S. Sperling, Nathanael S. Gray, Eric S. Fischer, Benjamin Ebert
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Cell Press
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Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy - Nature Genetics
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Abstract With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known.
By Jie Liu, Duc Thanh Tran, Caroline Watson, Mesbah Uddin, Abhishek Niroula, Gabriel K. Griffin, Benjamin Ebert, Taralynn M. Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ross Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H. Stopsack, Yin Cao, Matthew Walter, Nilanjan Chatterjee, Lucy A. Godley, Daniel Link, Zsofia K. Stadler
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Nature
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A heterotrimeric protein complex assembles the metazoan V-ATPase upon dissipation of proton gradients - Nature Structural & Molecular Biology
Abstract Organelles such as lysosomes and synaptic vesicles are acidified by V-ATPases, which consist of a cytosolically oriented V1 complex that hydrolyzes ATP and a membrane-embedded VO complex that pumps protons. In yeast, V1–VO association is facilitated by the RAVE (regulator of H+-ATPase of the vacuolar and endosomal membrane) complex, but how higher eukaryotes assemble V-ATPases remains unclear.
Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen
Keywords clonal hematopoiesis CHIP DNMT3A sex female estrogen hormones Esr1 HSC stem cell Research topic(s) CP: Stem cell research Introduction The risk of many cancers is markedly different between females and males, but the biological bases for these sex differences are incompletely understood.1,2,3 Male sex is associated with a higher incidence of most cancer types, including blood cancers.1,4 In some cases, the sex bias of blood cancers is associated with mutations on the sex...
Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression
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1Division of Clinical Immunology & Rheumatology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 2CAMBAC (Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center), University of Alabama at Birmingham, Birmingham, CA, USA 3Division of Rheumatology, Allergy, and Immunology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, San Diego, CA, USA 4Department of Cellular and Molecular Medicine, University of California,...
By Isidoro Cobo, Jessica Murillo, Mohnish Alishala, Stephen Calderon, Roxana Coras, Benjamin Hemming, Faith Inkum, Fiorella Rosas, Riku Takei, Nathan Spann, Paulo V.G. Alabarse, Se-Jin Jeong, Christian K Nickl, Anyan Cheng, Benjamin Li, Andrea Vogel, Thomas Weichhart, José J. Fuster, Thomas K. Le, Tara R Bradstreet, Ashlee Webber, Brian T. Edelson, Babak Razani, Benjamin Ebert, Reshma Taneja, Robert Terkeltaub, Ru Liu Bryan, Monica Guma, Christopher K. Glass
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Cell Press
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Mosaic chromosomal alterations (mCAs) in individuals with monoclonal B-cell lymphocytosis (MBL) - Blood Cancer Journal
Abstract MBL is a precursor condition to chronic lymphocytic leukemia (CLL), characterized by monoclonal B-cells in blood. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis that include gains, losses, and copy-neutral loss-of-heterozygosity of large DNA segments. Both MBL and mCAs have been found to increase the risk of CLL and lymphoid malignancies, and the aim of our study was to investigate how mCAs relate to MBL, which is currently unknown.
Author Correction: Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9 - Nature Medicine
Correction to: Nature Medicine https://doi.org/10.1038/nm.4047, published online 15 February 2016. In the version of the article initially published, the micrograph labeled #8840 in Supplementary Fig. 6a was a duplicate of the micrograph labelled #8900, also shown in the figure. A revised Supplementary information file accompanies the online version of this notice and includes the corrected #8840 micrograph.
Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis - Nature Communications
Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years.
Dana-Farber president announces intention to step down, successor named
You've successfully added Leukemia to your alerts. You will receive an email when new content is published. Click Here to Manage Email Alerts We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com. Laurie H. Glimcher, MD, announced her intention to step down as president and CEO of Dana-Farber Cancer Institute on Oct. 1.
A new track for KDELivery of designer cargo by platelets
A new track for KDELivery of designer cargo by platelets • None Targeting cargo to an unconventional secretory system within megakaryocytes allows the release of transgenic proteins from platelets • None Platelet-derived drug delivery systems: pioneering treatment for cancer, cardiovascular diseases, infectious diseases, and beyond • None The endoplasmic reticulum: structure, function and response to cellular signaling • None KDEL Receptors are differentially regulated to maintain the ER...
Targeted protein degradation: from mechanisms to clinic - Nature Reviews Molecular Cell Biology
Abstract Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation.
The Impact of Structural Pattern Types on the Electrochemical Performance of Ultra-Thick NMC 622 Electrodes for Lithium-Ion Batteries
All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess.
Induced protein degradation for therapeutics: past, present, and future
Pharmacological manipulation of the ubiquitin-proteasome system The majority of induced protein degradation engages the ubiquitin-proteasome system. This pathway leverages a posttranslational modification – the covalent attachment of ubiquitin to a substrate protein through the coordinated, sequential activity of three classes of enzymes (22). First, an E1 ubiquitin-activating enzyme utilizes ATP to adenylate ubiquitin and establish a thioester bond between ubiquitin and the E1 enzyme.
Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7 - Leukemia
Abstract CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities.
Proteolysis-targeting chimeras with reduced off-targets - Nature Chemistry
Abstract Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease.
Design principles for cyclin K molecular glue degraders - Nature Chemical Biology
Abstract Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase.
Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes - Nature Cardiovascular Research
Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans.
Author Correction: Clonal haematopoiesis and risk of chronic liver disease - Nature
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Correction to: Nature https://doi.org/10.1038/s41586-023-05857-4 Published online 12 April 2023 In the version of the article originally published, Extended Data Figure 4a was an inadvertent duplicate of Extended Data Figure 4b and has now been corrected in the HTML and PDF versions of the article. Author information Author notes These authors contributed equally: Waihay J. Wong, Connor Emdin These authors jointly supervised this work: Benjamin L.
By Waihay J. Wong, Seyedeh M Zekavat, James P Pirruccello, Mesbah Uddin, Christopher Gibson, Amélie Vromman, Peter Kim, Joshua Weinstock, Michelle Long, Rowan C. Nicholls, Matt Kelly, Po-Ru Loh, Steve McCarroll, Ramachandran S. Vasan, Siddhartha Jaiswal, Andrew Johnson, Daniel Levy, Christie M. Ballantyne, Benjamin Ebert
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Nature
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RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia - Leukemia
Author notes These authors contributed equally: William Marion, Tiago Koppe. Authors and Affiliations Department of Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA William Marion, Tiago Koppe, Dahai Wang, Katie Frenis, Sara Fierstein, Prerana Sensharma, Olivia Aumais, Michael Peters, Akiko Shimamura, Daniel E. Bauer & R.
Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias - Nature Cancer
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Abstract Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies that have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages.
By Benjamin Barwick, Vikas Gupta, Yiguo Hu, Jordan G Bryan, Andrew J. Aguirre, Benjamin Ebert, Christopher J. Ott, James E. Bradner, Jonathan Keats, Nathanael S. Gray, Aedín C. Culhane, James M McFarland, Joshua M. Dempster, Jonathan D. Licht, Lawrence Boise, William Hahn, Francisca Vazquez, Aviad Tsherniak
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Nature
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Clonal haematopoiesis and risk of chronic liver disease - Nature
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Abstract Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2.
By Waihay J. Wong, Seyedeh M Zekavat, James P Pirruccello, Mesbah Uddin, Christopher Gibson, Amélie Vromman, Peter Kim, Joshua Weinstock, Michelle Long, Matt Kelly, Po-Ru Loh, Steve McCarroll, Ramachandran S. Vasan, Siddhartha Jaiswal, Andrew Johnson, Daniel Levy, Christie M. Ballantyne, Benjamin Ebert, Rowan C. Nicholls
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Nature
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Clonal haematopoiesis and dysregulation of the immune system - Nature Reviews Immunology
Abstract Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells — a condition known as clonal haematopoiesis (CH) — are associated with ageing and pathological immune dysfunction.
TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease - Nature Cardiovascular Research
Author notes These authors contributed equally: Seyedeh M. Zekavat, Vanesa Viana-Huete, Nuria Matesanz. These authors jointly supervised this work: Pradeep Natarajan, Alexander G. Bick, José J. Fuster, Derek Klarin. Authors and Affiliations Department of Ophthalmology, Massachusetts Eye and Ear Institute, Boston, MA, USA Seyedeh M. Zekavat Computational Biology & Bioinformatics Program, Yale University, New Haven, CT, USA Seyedeh M.
Activity of menin inhibitor ziftomenib (KO-539) as monotherapy or in combinations against AML cells with MLL1 rearrangement or mutant NPM1 - Leukemia
To the Editor: In MLL1-rearranged AML (MLL1-r), the MLL1 fusion protein (MLL-FP) causes dysregulated expression of HOXA9, MEIS1, PBX3, MEF2C and CDK6 [1, 2]. HOXA9 and its co-factor MEIS1 are leukemogenic in myeloid stem progenitor cells [3,4,5]. Additionally, in AML with mtNPM1 (NPM1c), MLL1 is the main oncogenic regulator of HOXA9, MEIS1 and FLT3, promoting self-renewal of myeloid progenitor cells [2, 6, 7].
Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease - Nature Communications
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Abstract Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes.
By Jennifer Brody, Akhil Pampana, Tetsushi Nakao, Myriam Fornage, Jan Bressler, Joshua Weinstock, Michael C. Honigberg, Daniel Nachun, Andrea A. Baccarelli, Daniel I. Chasman, Eric A. Whitsel, Douglas P Kiel, Benjamin Ebert, Siddhartha Jaiswal, Alexander Bick, Christie M. Ballantyne, Bruce M. Psaty, Pradeep Natarajan
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Nature
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Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state - Nature Communications
Abstract PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity.
Blood’s life history traced through genomic scars
Humans produce roughly two million blood cells each second, derived from a relatively small pool of haematopoietic stem cells (HSCs). Over a lifetime, each HSC accumulates mutations in its DNA, some of which confer a competitive advantage on the cell and its descendants. The result is a phenomenon known as clonal haematopoiesis, which leads to an expanded pool of blood cells descended from the same HSC.
Leukemia and Heart Disease: Lessons at the Intersection of the Most Feared CHIP Outcomes∗
Introduction Mutant blood cells can be associated with both malignant and nonmalignant outcomes.
The impact of the COVID-19 pandemic on cancer care
The COVID-19 pandemic has disrupted the spectrum of cancer care, including delaying diagnoses and treatment and halting clinical trials. In response, healthcare systems are rapidly reorganizing cancer services to ensure that patients continue to receive essential care while minimizing exposure to SARS-CoV-2 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19), continues to spread globally at an alarming rate.
Rapid and deep-scale ubiquitylation profiling for biology and translational research
Abstract Protein ubiquitylation is involved in a plethora of cellular processes. While antibodies directed at ubiquitin remnants (K-ɛ-GG) have improved the ability to monitor ubiquitylation using mass spectrometry, methods for highly multiplexed measurement of ubiquitylation in tissues and primary cells using sub-milligram amounts of sample remains a challenge.
Clonal hematopoiesis in human aging and disease
Cryptic signs of aging in our blood Time is not a friend to our DNA. Aging is associated with an accumulation of somatic mutations in normal dividing cells, including the hematopoietic stem cells (HSCs) that give rise to all blood cells. Certain mutations in HSCs confer a fitness advantage that results in clonal expansions of mutant blood cells that sometimes—but not always—forecast the development of cancer and other age-related diseases.
Predicting progression to AML
The number, identity, and burden of mutations in clonal hematopoiesis are associated with the risk and timing of progression to acute myeloid leukemia.
Clonal Hematopoiesis Confers Predisposition to Both Cardiovascular Disease and Cancer: A Newly Recognized Link Between Two Major Killers
Two scourges of humanity seem to have heretofore unsuspected common roots: cancer and cardiovascular disease. These seemingly disparate disorders share strong associations with aging. As we age, our cells can accumulate somatic genetic mutations, some of which are established drivers of cancer.
Broad Institute and Deerfield Management Announce the Advancement of Two Partnership Projects
CAMBRIDGE, Mass. and NEW YORK, Feb. 6, 2018 /PRNewswire/ -- The Broad Institute of MIT and Harvard and Deerfield Management announced today the advancement of two projects through their first-of-its-kind research partnership, which is aimed at solving complex, early-stage therapeutic challenges related to serious unmet medical needs.
Broad Institute and Deerfield Management Announce the Advancement of Two Partnership Projects
"Now that we have identified the biological roots of certain types of drug resistance in cancer, we are working to develop a therapeutic intervention," Ebert said. "Our partnership with Deerfield allows us to advance this research far more rapidly than we would otherwise, and move the research closer to the clinic." Benjamin Ebert is an institute member of the Broad Institute, a professor of medicine at Harvard Medical School, and chair of medical oncology at the Dana-Farber Cancer Institute.
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