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Clinical MedicineIn-Press PreviewTransplantation Open Access | 10.1172/JCI163541

Chronic graft versus host disease detected by tissue-specific cell-free DNA methylation biomarkers

Batia Avni,1 Daniel Neiman,2 Elior D. Shaked,2 Ofer Gal-Rosenberg,2 Sigal Grisariu,1 Mona Kuzli,1 Ilai Avni,3 Andrea Fracchia,1 Polina Stepensky,1 Tsila Zuckerman,4 Ahinoam Lev-Sagie,5 Ilana Fox-Fisher,2 Sheina Piyanzin,2 Joshua Moss,6 Seth J. Salpeter,2 Benjamin Glaser,7 Ruth Shemer,2 and Yuval Dor2

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Avni, B. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Neiman, D. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Shaked, E. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Gal-Rosenberg, O. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Grisariu, S. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Kuzli, M. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Avni, I. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Fracchia, A. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Stepensky, P. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Zuckerman, T. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Lev-Sagie, A. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Fox-Fisher, I. in: JCI | PubMed | Google Scholar |

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Piyanzin, S. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Moss, J. in: JCI | PubMed | Google Scholar |

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Salpeter, S. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Glaser, B. in: JCI | PubMed | Google Scholar |

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Shemer, R. in: JCI | PubMed | Google Scholar

1Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

2Department of Developmental Biology and Cancer Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

3Faculty of Data and Decision Sciences, Institute of Technology - Technion, Haifa, Israel

4Hematology Department and Bone Marrow Transplantation Unit, Rambam Health Care Campus, Haifa, Israel

5Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

6Hadassah-Hebrew University Medical Center, Jerusalem, Israel

7Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Find articles by Dor, Y. in: JCI | PubMed | Google Scholar |

Published November 16, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI163541.
Copyright © 2023, Avni et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 16, 2023 - Version history
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Abstract

BACKGROUND. Accurate detection of graft versus host disease (GVHD) is a major challenge in the management of patients that undergo hematopoietic stem cell transplantation (HCT). Here we demonstrate the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic GVHD (cGVHD) in specific organs.

METHODS. We established a cocktail of tissue-specific DNA methylation markers and used it to determine the concentration of cfDNA molecules derived from the liver, skin, lungs, colon and specific immune cells in 101 HCT patients. Results: Patients with an active cGVHD showed elevated concentration of cfDNA, as well as tissue-specific methylation markers that agreed with clinical scores. Strikingly, transplanted patients with no clinical symptoms had abnormally high levels of tissue-specific markers, suggesting hidden tissue turnover even in the absence of evident clinical pathology. An integrative model taking into account total cfDNA concentration, monocyte/macrophage cfDNA levels and Alanine transaminase (ALT) was able to correctly identify GVHD with a specificity of 86% and precision of 89% (AUC of 0.8).

CONCLUSIONS. cfDNA markers can be used for the detection of cGVHD, opening a window into underlying tissue dynamics in patients that receive allogeneic stem cell transplants.

FUNDING. This work was supported by grants from the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Israel Science Foundation, the Waldholtz / Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation and the Helmsley Charitable Trust (to Y.D).

Graphical Abstract
graphical abstract
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  • Version 1 (November 16, 2023): In-Press Preview
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