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Rosai-Dorfman Disease: Atlas of Blood Cancer Genomes

Rosai-Dorfman disease (RDD) is a rare histiocytic disorder, most prevalent in children and young adults. The diagnosis of RDD and other histiocytic disorders including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) can be challenging as it relies mostly on immunohistochemistry (IHC) of infrequently assayed markers. Little is known about how the gene expression profiles of histiocytic disorders correlate with IHC diagnostic markers, activation of different oncogenic pathways, or components of the microenvironment. To address this gap, we performed whole transcriptome sequencing on samples from 23 RDD, 4 ECD and 9 LCH patients, enabling us to examine differential gene expression, tumor microenvironment signatures and gene set enrichment between the different histiocytic neoplasms. Gene expression levels by RNA sequencing correlated well with IHC results for diagnostic markers for all three diseases, highlighting the ability to use RNA-based approaches including RNAseq for diagnosing these tumors. RDD samples showed strong 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 HNFA3A pathway. Cell type deconvolution showed 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 the utility of RNA sequencing in helping to distinguish histiocytic disorders, as well as differential activation of oncogenic pathways and tumor microenvironment between RDD, ECD and LCH, that sheds light on the pathogenesis and overall disease biology of these rare disorders.