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

• Type of Material: Article
• Authors: Martin A Rivas, Weill Cornell Medicine; Ceyda Durmaz, Weill Cornell Medicine; Andreas Kloetgen, Helmholtz Centre for Infection Research; Cristopher R Chin, Weill Cornell Medicine; Zhengming Chen, Weill Cornell Medical College; Bhavneet Bhinder, Weill Cornell Medicine; Amnon Koren, Cornell University; Aaron D Viny, Columbia University; Christopher Scharer, Emory University; Jeremy Boss, Emory University; Olivier Elemento, Weill Cornell Medicine; Christopher E Mason, Weill Cornell Medicine; Ari M Melnick, Weill Cornell Medicine
• Language: English
• Date: 2021-09-21
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Rivas, Durmaz, Kloetgen, Chin, Chen, Bhinder, Koren, Viny, Scharer, Boss, Elemento, Mason and Melnick
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.688493
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 688493
• End Page: 688493
• Grant/Funding Information: AV is supported by NCI K08 CA215317, the William Raveis Charitable Fund Fellowship of the Damon Runyon Cancer Research Foundation (DRG 117-15) and an Evans MDS Young Investigator grant from the Edward P. Evans Foundation.; MR was a recipient of a postdoctoral fellowship grant from the Lymphoma Research Foundation and is funded by an NHLBI 5 T32 HL135465-3 training grant.; AM is supported by NCI/NIH R35 CA220499, NCI/NIH P01 CA229086-01A1, LLS-SCOR 7012-16, LLS-TRP 6572-19, the Samuel Waxman Cancer Research Foundation, the Follicular Lymphoma Consortium and the Chemotherapy Foundation.; AKo is supported by DP2GM123495 from the National Institutes of Health.; CM thanks the Scientific Computing Unit, XSEDE Supercomputing Resources as well as the Starr Cancer Consortium (I7-A765, I9-A9- 071 and I13-0052) and acknowledges funding from the WorldQuant Foundation, The Pershing Square Sohn Cancer Research Alliance, the NIH (grants R01 CA249054, R01 AI151059, P01 CA214274, R01 AI125416-03 and R21 AI129851-02) and Leukemia and Lymphoma Society grants LLS 9238-16 and LLS MCL-982.
• Keywords: Tet2 gene; BLADDER-CANCER; MUTATIONS; B-cell; Immunology; GCB-subtype DLBCL; EXPRESSION; B-CELL LYMPHOMA; Life Sciences & Biomedicine; ORIGIN; STAG2; cohesin; chromosomal architecture; lymphoma; CHROMATID COHESION; HUMAN GENOME; INACTIVATION; Hi-C; PROGRAM; Science & Technology

Abstract

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.