High-throughput approaches to uncover synergistic drug combinations in leukemia

Emma J. Chory; Meng Wang; Michele Ceribelli; Aleksandra M Michalowska; Stefan Golas; Erin Beck; Carleen Klumpp-Thomas; Lu Chen; Crystal McKnight; Zina Itkin; Kelli M. Wilson; David Holland; Sanjay Divakaran; James Bradner; Javed Khan; Berkley E. Gryder; Craig J. Thomas; Benjamin Z. Stanton

SLAS Discovery (Jun 2023)

High-throughput approaches to uncover synergistic drug combinations in leukemia

Emma J. Chory,
Meng Wang,
Michele Ceribelli,
Aleksandra M Michalowska,
Stefan Golas,
Erin Beck,
Carleen Klumpp-Thomas,
Lu Chen,
Crystal McKnight,
Zina Itkin,
Kelli M. Wilson,
David Holland,
Sanjay Divakaran,
James Bradner,
Javed Khan,
Berkley E. Gryder,
Craig J. Thomas,
Benjamin Z. Stanton

Affiliations

Emma J. Chory: Media Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Corresponding authors.
Meng Wang: Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH, USA.
Michele Ceribelli: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Aleksandra M Michalowska: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Stefan Golas: Media Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Erin Beck: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Carleen Klumpp-Thomas: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Lu Chen: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Crystal McKnight: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Zina Itkin: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Kelli M. Wilson: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
David Holland: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.
Sanjay Divakaran: Cardio-Oncology Program, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
James Bradner: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Javed Khan: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Berkley E. Gryder: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio 44106, United States.
Craig J. Thomas: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD 20850, USA.; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Benjamin Z. Stanton: Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Biological Chemistry & Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USA.; Corresponding authors.

Journal volume & issue: Vol. 28, no. 4
pp. 193 – 201

Abstract

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ABSTRACT: We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community.

Published in SLAS Discovery

ISSN: 2472-5552 (Print); 2472-5560 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General); Technology: Chemical technology: Biotechnology
Website: https://www.journals.elsevier.com/slas-discovery

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Abstract

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