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Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis

J. Brett Heimlich, Pawan Bhat, Alyssa C. Parker, Matthew T. Jenkins, Caitlyn Vlasschaert, Jessica Ulloa, Chad R. Potts, Sydney Olson, Alexander J. Silver, Ayesha Ahmad, Brian Sharber, Donovan Brown, Ningning Hu, View ORCID ProfilePeter van Galen, Michael R. Savona, Alexander G. Bick, P. Brent Ferrell
doi: https://doi.org/10.1101/2022.12.01.518580
J. Brett Heimlich
1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Pawan Bhat
2Vanderbilt University School of Medicine, Nashville, TN 37232
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Alyssa C. Parker
2Vanderbilt University School of Medicine, Nashville, TN 37232
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Matthew T. Jenkins
2Vanderbilt University School of Medicine, Nashville, TN 37232
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Caitlyn Vlasschaert
3Department of Medicine, Queen’s University, Kingston Ontario, Canada
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Jessica Ulloa
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Chad R. Potts
5Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Sydney Olson
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Alexander J. Silver
2Vanderbilt University School of Medicine, Nashville, TN 37232
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Ayesha Ahmad
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Brian Sharber
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Donovan Brown
5Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Ningning Hu
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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Peter van Galen
6Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115 USA
7Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA
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  • ORCID record for Peter van Galen
Michael R. Savona
5Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
8Vanderbilt-Ingram Cancer Center, Program in Cancer Biology, and Center for Immunobiology Nashville, TN 37232
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Alexander G. Bick
4Division of Genomic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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  • For correspondence: alexander.bick@vumc.org brent.ferrell@vumc.org
P. Brent Ferrell
5Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
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  • For correspondence: alexander.bick@vumc.org brent.ferrell@vumc.org
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Abstract

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to increase cardiovascular disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 104,566 single cells from a cohort of 17 CH patients and 6 controls. We discovered that patients harboring DNMT3A and TET2 CH mutations at baseline and in response to IL-6 stimulation confer a pro-inflammatory profile to CD14+ monocytes through previously unrecognized pathways including Macrophage Inhibitory Factor (MIF). A germline genetic variant in MIF modifies TET2 CH cardiovascular disease risk. Using mitochondrial lineage tracing, we used a novel method to compare gene expression between mutated and non-mutated cells within individual CH patients. We found that the mutated CH monocytes, but not non-mutated monocytes are pro-inflammatory, explaining why patients with larger CH clones have increased cardiovascular disease risk.

Competing Interest Statement

All unrelated to the present work: M.R.S. reports personal fees from AbbVie, BMS, CTI, Sierra Oncology, Novartis, grants from Astex and Incyte, personal fees and other support from Karyopharm, Ryvu, personal fees from Sierra Oncology, grants and personal fees from Takeda, and TG Therapeutics outside the submitted work. P.B.F. reports grants from Incyte. A.G.B. is a scientific co-founder and has equity in TenSixteen Bio. All other authors declare that they have no competing interests.

Footnotes

  • This revision was posted to accommodate the biorxiv watermark across figures.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis
J. Brett Heimlich, Pawan Bhat, Alyssa C. Parker, Matthew T. Jenkins, Caitlyn Vlasschaert, Jessica Ulloa, Chad R. Potts, Sydney Olson, Alexander J. Silver, Ayesha Ahmad, Brian Sharber, Donovan Brown, Ningning Hu, Peter van Galen, Michael R. Savona, Alexander G. Bick, P. Brent Ferrell
bioRxiv 2022.12.01.518580; doi: https://doi.org/10.1101/2022.12.01.518580
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Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis
J. Brett Heimlich, Pawan Bhat, Alyssa C. Parker, Matthew T. Jenkins, Caitlyn Vlasschaert, Jessica Ulloa, Chad R. Potts, Sydney Olson, Alexander J. Silver, Ayesha Ahmad, Brian Sharber, Donovan Brown, Ningning Hu, Peter van Galen, Michael R. Savona, Alexander G. Bick, P. Brent Ferrell
bioRxiv 2022.12.01.518580; doi: https://doi.org/10.1101/2022.12.01.518580

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