Cohesin Core Complex Gene Dosage Contributes to Germinal Center Derived Lymphoma Phenotypes and Outcomes

Frontiers in Immunology

Jeremy M. Boss¹  Andreas Kloetgen²  Christopher D. Scharer³  Ari M. Melnick⁵  Amnon Koren⁶  Olivier Elemento⁹  Cristopher R. Chin⁹  Martin A. Rivas^1,11  Aaron D. Viny^1,12  Ceyda Durmaz^1,13  Zhengming Chen^1,14  Bhavneet Bhinder^1,14  Christopher E. Mason^1,14 

[1] Development, Columbia University, New York, NY, United States;Systems Biology, Weill Cornell Medicine, New York, NY, United States;;0Columbia Stem Cell Initiative, Department of Genetics &1Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, United States;2The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, United States;Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, United States;Department of Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, United States;Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, United States;Division of Biostatistics and Epidemiology, Department of Population Health Sciences, Weill Cornell Medical College, New York, NY, United States;Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, United States;Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States;;Graduate Program on Physiology, Biophysics &The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, United States;

关键词: cohesin;    lymphoma;    B-cell;    chromosomal architecture;    Hi-C;    Tet2 gene;   

DOI  :  10.3389/fimmu.2021.688493

来源: DOAJ

【 摘 要 】

The cohesin complex plays critical roles in genomic stability and gene expression through effects on 3D architecture. Cohesin core subunit genes are mutated across a wide cross-section of cancers, but not in germinal center (GC) derived lymphomas. In spite of this, haploinsufficiency of cohesin ATPase subunit Smc3 was shown to contribute to malignant transformation of GC B-cells in mice. Herein we explored potential mechanisms and clinical relevance of Smc3 deficiency in GC lymphomagenesis. Transcriptional profiling of Smc3 haploinsufficient murine lymphomas revealed downregulation of genes repressed by loss of epigenetic tumor suppressors Tet2 and Kmt2d. Profiling 3D chromosomal interactions in lymphomas revealed impaired enhancer-promoter interactions affecting genes like Tet2, which was aberrantly downregulated in Smc3 deficient lymphomas. Tet2 plays important roles in B-cell exit from the GC reaction, and single cell RNA-seq profiles and phenotypic trajectory analysis in Smc3 mutant mice revealed a specific defect in commitment to the final steps of plasma cell differentiation. Although Smc3 deficiency resulted in structural abnormalities in GC B-cells, there was no increase of somatic mutations or structural variants in Smc3 haploinsufficient lymphomas, suggesting that cohesin deficiency largely induces lymphomas through disruption of enhancer-promoter interactions of terminal differentiation and tumor suppressor genes. Strikingly, the presence of the Smc3 haploinsufficient GC B-cell transcriptional signature in human patients with GC-derived diffuse large B-cell lymphoma (DLBCL) was linked to inferior clinical outcome and low expression of cohesin core subunits. Reciprocally, reduced expression of cohesin subunits was an independent risk factor for worse survival int DLBCL patient cohorts. Collectively, the data suggest that Smc3 functions as a bona fide tumor suppressor for lymphomas through non-genetic mechanisms, and drives disease by disrupting the commitment of GC B-cells to the plasma cell fate.

【 授权许可】

Unknown