1. Loss of function mutations of BCOR in classical Hodgkin lymphoma.
- Author
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Giefing M, Gearhart MD, Schneider M, Overbeck B, Klapper W, Hartmann S, Ustaszewski A, Weniger MA, Wiehle L, Hansmann ML, Melnick A, Béguelin W, Sundström C, Küppers R, Bardwell VJ, and Siebert R
- Subjects
- Animals, Humans, Loss of Function Mutation, Mice, Mutation, Polycomb Repressive Complex 1 metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Reed-Sternberg Cells pathology, Repressor Proteins genetics, Repressor Proteins metabolism, Hodgkin Disease pathology
- Abstract
BCOR is a component of a variant Polycomb repressive complex 1 (PRC1.1). PRC1 and PRC2 complexes together constitute a major gene regulatory system critical for appropriate cellular differentiation. The gene is upregulated in germinal center (GC) B cells and mutated in a number of hematologic malignancies. We report BCOR inactivating alterations in 4/7 classic Hodgkin lymphoma (cHL) cell lines, subclonal somatic mutations in Hodgkin and Reed-Sternberg (HRS) cells of 4/10 cHL cases, and deletions in HRS cells of 7/17 primary cHL cases. In mice, conditional loss of Bcor driven by AID-Cre in GC B cells resulted in gene expression changes of 46 genes (>2-fold) including upregulated Lef1 that encodes a transcription factor responsible for establishing T-cell identity and Il9r (interleukin-9 receptor), an important member of the cytokine network in cHL. Our findings suggest a role for BCOR loss in cHL pathogenesis and GC-B cell homeostasis.
- Published
- 2022
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