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Peer-reviewedCC BY 4.0Cancer Research Communications

Elucidating the Gene Expression Signature of Rosai–Dorfman Disease: A Study from the Atlas of Blood Cancer Genomes Initiative

  • Sheren Younes1
  • Fadzai Chinyengetere2
  • Veronica Russell2
  • Devang Thakkar3
  • Emily F. Mason4
  • Ridas Juskevicius5,6
  • Alexandra E. Kovach5
  • Shaoying Li7
  • C. Cameron Yin7
  • Dennis P. O’Malley8
  • Jean L. Koff9
  • David L. Jaye10
22 more authors
  • Cassandra Love2
  • Jennifer R. Shingleton2
  • Dennis Owusu2
  • Ayush Batra2
  • Leonardo P.A. Biral2
  • Elizabeth Thacker3
  • Clay Parker3
  • Lanie Happ3
  • Jennifer Chapman Fredricks11,12
  • Izidore S. Lossos12,13
  • Sarah L. Ondrejka14
  • Eric Hsi15
  • Eric Tse16
  • Rex K.H. Au-Yeung17
  • Govind Bhagat18
  • Rebecca J. Leeman-Neill19
  • Amy Chadburn20
  • Magdalena Czader21
  • Yuri Fedoriw22
  • Kikkeri N. Naresh23
  • Sandeep S. Dave2
  • Yasodha Natkunam24
24 affiliations
  1. 1Stanford University, Palo Alto, California.
  2. 2Duke University, Durham, North Carolina.
  3. 3Data Driven Bioscience, Durham, North Carolina.
  4. 4Division of Hematopathology, Vanderbilt University, Nashville, Tennessee.
  5. 5Vanderbilt University Medical Center, Nashville, Tennessee.
  6. 6PathGroup, Nashville, Tennessee.
  7. 7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  8. 8NeoGenomics, Fort Myers, Florida.
  9. 9Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
  10. 10Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
  11. 11Department of Pathology, University of Miami, Miami, Florida.
  12. 12Sylvester Comprehensive Cancer Center, Miami, Florida.
  13. 13Division of Hematology, Department of Medicine, University of Miami, Miami, Florida.
  14. 14Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
  15. 15Mayo Clinic, Rochester, Minnesota.
  16. 16University of Hong Kong, Hong Kong, Hong Kong SAR, China.
  17. 17Department of Pathology, University of Hong Kong, Hong Kong, Hong Kong SAR, China.
  18. 18Department of Pathology, Saint Louis University School of Medicine, SSM Health, Saint Louis, Missouri.
  19. 19Department of Pathology and Laboratory Medicine, Columbia University Medical Center, New York, New York.
  20. 20Department of Pathology, Weill Cornell Medical College, New York, New York.
  21. 21Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana.
  22. 22University of North Carolina, Chapel Hill, North Carolina.
  23. 23Pathology Program, Translational Science and Therapeutics Division, Department of Pathology, Fred Hutchinson Cancer Center, Seattle, Washington.
  24. 24Stanford University Medical Center, Palo Alto, California.
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Abstract

Rosai–Dorfman disease (RDD) is a rare histiocytic disorder characterized by the accumulation of large histiocytes in nodal and/or extranodal sites. The underlying biology of RDD and factors that distinguish it from other histiocyte disorders are poorly understood. To better understand the disease biology, we employed whole-transcriptome RNA sequencing (RNA-seq) to study the gene expression profiles of RDD as part of the Atlas of Blood Cancer Genomes (ABCG) initiative. Gene expression profiles of RDD (N = 23) were then compared with two other histiocytoses [Langerhans cell histiocytosis (LCH; N = 15) and Erdheim–Chester disease (ECD; N = 4)], which are most often considered in the clinicopathologic differential diagnosis of RDD. We found that gene expression levels by RNA-seq correlated well with known immunohistochemistry results for diagnostic markers for all three diseases, highlighting the ability to use RNA-based approaches for the diagnosis of these tumors. RDD samples showed enrichment of gene sets related to B cells and the IL27 pathway. In contrast, LCH showed enrichment of gene sets related to resting dendritic cells and the HNF3A pathway. We found significant differences in the composition of the microenvironment, with an enrichment of memory B cells, plasma cells, and CD8 T cells in the RDD microenvironment and enrichment of dendritic cells in the LCH microenvironment. In summary, our study demonstrates unique gene expression signatures in RDD that show overlap as well as distinctive patterns from LCH or ECD. These novel gene expression signatures encompass pathways that could potentially contribute to the pathogenesis and targeted treatment of this rare histiocytic entity.

Significance:: To our knowledge, this study is the first to report that protein expression of markers used in the immunohistochemical diagnosis of RDD and other histiocytoses correlates well with gene expression. This finding indicates that RNA-based methods can be used in the clinical diagnosis of RDD. We also demonstrate that RDD shows a unique tumor microenvironment that is rich in immune cells, including B cells, plasma cells, and CD8+ T cells.

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Cite

BibTeXRIS
BibTeX
@article{younes2026elucidating,
  title = {{Elucidating the Gene Expression Signature of Rosai–Dorfman Disease: A Study from the Atlas of Blood Cancer Genomes Initiative}},
  author = {Sheren Younes and Fadzai Chinyengetere and Veronica Russell and Devang Thakkar and Emily F. Mason and Ridas Juskevicius and Alexandra E. Kovach and Shaoying Li and C. Cameron Yin and Dennis P. O’Malley and Jean L. Koff and David L. Jaye and Cassandra Love and Jennifer R. Shingleton and Dennis Owusu and Ayush Batra and Leonardo P.A. Biral and Elizabeth Thacker and Clay Parker and Lanie Happ and Jennifer Chapman Fredricks and Izidore S. Lossos and Sarah L. Ondrejka and Eric Hsi and Eric Tse and Rex K.H. Au-Yeung and Govind Bhagat and Rebecca J. Leeman-Neill and Amy Chadburn and Magdalena Czader and Yuri Fedoriw and Kikkeri N. Naresh and Sandeep S. Dave and Yasodha Natkunam},
  journal = {Cancer Research Communications},
  year = {2026},
  month = oct,
  doi = {10.1158/2767-9764.crc-25-0834},
  url = {https://doi.org/10.1158/2767-9764.crc-25-0834},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Elucidating the Gene Expression Signature of Rosai–Dorfman Disease: A Study from the Atlas of Blood Cancer Genomes Initiative
AU  - Sheren Younes
AU  - Fadzai Chinyengetere
AU  - Veronica Russell
AU  - Devang Thakkar
AU  - Emily F. Mason
AU  - Ridas Juskevicius
AU  - Alexandra E. Kovach
AU  - Shaoying Li
AU  - C. Cameron Yin
AU  - Dennis P. O’Malley
AU  - Jean L. Koff
AU  - David L. Jaye
AU  - Cassandra Love
AU  - Jennifer R. Shingleton
AU  - Dennis Owusu
AU  - Ayush Batra
AU  - Leonardo P.A. Biral
AU  - Elizabeth Thacker
AU  - Clay Parker
AU  - Lanie Happ
AU  - Jennifer Chapman Fredricks
AU  - Izidore S. Lossos
AU  - Sarah L. Ondrejka
AU  - Eric Hsi
AU  - Eric Tse
AU  - Rex K.H. Au-Yeung
AU  - Govind Bhagat
AU  - Rebecca J. Leeman-Neill
AU  - Amy Chadburn
AU  - Magdalena Czader
AU  - Yuri Fedoriw
AU  - Kikkeri N. Naresh
AU  - Sandeep S. Dave
AU  - Yasodha Natkunam
PY  - 2026
DA  - 2026/10/30
JO  - Cancer Research Communications
DO  - 10.1158/2767-9764.crc-25-0834
UR  - https://doi.org/10.1158/2767-9764.crc-25-0834
AB  - Rosai–Dorfman disease (RDD) is a rare histiocytic disorder characterized by the accumulation of large histiocytes in nodal and/or extranodal sites. The underlying biology of RDD and factors that distinguish it from other histiocyte disorders are poorly understood. To better understand the disease biology, we employed whole-transcriptome RNA sequencing (RNA-seq) to study the gene expression profiles of RDD as part of the Atlas of Blood Cancer Genomes (ABCG) initiative. Gene expression profiles of RDD (N = 23) were then compared with two other histiocytoses [Langerhans cell histiocytosis (LCH; N = 15) and Erdheim–Chester disease (ECD; N = 4)], which are most often considered in the clinicopathologic differential diagnosis of RDD. We found that gene expression levels by RNA-seq correlated well with known immunohistochemistry results for diagnostic markers for all three diseases, highlighting the ability to use RNA-based approaches for the diagnosis of these tumors. RDD samples showed enrichment of gene sets related to B cells and the IL27 pathway. In contrast, LCH showed enrichment of gene sets related to resting dendritic cells and the HNF3A pathway. We found significant differences in the composition of the microenvironment, with an enrichment of memory B cells, plasma cells, and CD8 T cells in the RDD microenvironment and enrichment of dendritic cells in the LCH microenvironment. In summary, our study demonstrates unique gene expression signatures in RDD that show overlap as well as distinctive patterns from LCH or ECD. These novel gene expression signatures encompass pathways that could potentially contribute to the pathogenesis and targeted treatment of this rare histiocytic entity.  Significance:: To our knowledge, this study is the first to report that protein expression of markers used in the immunohistochemical diagnosis of RDD and other histiocytoses correlates well with gene expression. This finding indicates that RNA-based methods can be used in the clinical diagnosis of RDD. We also demonstrate that RDD shows a unique tumor microenvironment that is rich in immune cells, including B cells, plasma cells, and CD8+ T cells.
SN  - 2767-9764
ER  -