Loss of function mutations of BCOR in classical Hodgkin lymphoma

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.

Keywords:

• Classical Hodgkin lymphoma
• microdissection
• BCOR
• Polycomb
• PRC1

Author contributions

M.G. performed the research, analyzed the data, wrote the paper and prepared the figures. M.D.G. performed the research, analyzed the data, wrote the paper and prepared the figures. M.S. performed the research and analyzed the data. B.O. performed the research. W.K. characterized the material and contributed essential tools. S.H. characterized the material and contributed essential tools. A.U. analyzed the data and prepared the figures. M.A.W. performed the research and analyzed the data. L.W. analyzed the data. M.L-H. characterized the material and contributed essential tools. A.M. performed the research, analyzed the data and contributed essential tools. W.B. performed the research and analyzed the data. C.S. characterized the material. R.K. analyzed the data, contributed essential tools and wrote the paper. V.J.B. designed the research study, analyzed the data, contributed essential tools and wrote the paper. R.S. designed the research study, analyzed the data, contributed essential tools and wrote the paper.

Acknowledgements

The authors thank Reina Zühlke-Jenisch and Jennifer Ishii for excellent technical assistance. The authors thank Rafael Casellas for providing AID-Cre mice. We would also like to thank Justin Taylor for help with B cell enrichments.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

M.G. was supported by an FEBS Long-Term Fellowship and Support for International Mobility of Scientists fellowship of the Polish Ministry of Science and Higher Education. Support for infrastructure has been provided by the KinderKrebsInitiative Buchholz/Holm-Seppensen. R.K. and M.L-H. were supported by the Wilhelm Sander Stiftung [2018.101.1] and the DFG [KU1315/10-1]. M.D.G. and V.J.B. were supported by the NIH [5R01CA071540] and funds from the Minnesota Masonic Charities, and the University of Minnesota Medical School and Office of the Vice President for Research. A.M. is supported by NCI R35 CA220499, the Chemotherapy Foundation, the Follicular Lymphoma Consortium, LLS SCOR 7012-16 and LLS TRP 6572-19. W.B. is supported by an American Society of Hematology Scholar Award. R.S. and M.G. received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 952304. The work in the group of RS was in part supported by DFG trough SFB 1074 (project TP9N).