Transcriptomics,Genomics

Dataset Information

46

Divergent Mechanisms of Oncogenic B Cell Receptor Signaling in Lymphoma


ABSTRACT: B cell receptor (BCR) signaling has emerged as a therapeutic target in B cell lymphomas, but the precise deployment of inhibitors to target oncogenic BCR signaling requires detailed knowledge of the signaling cascades that the BCR triggers in individual tumors. Here, we have used CRISPR-Cas9 screens to investigate whether the ABC and GCB molecular subtypes of diffuse large B cell lymphoma (DLBCL) utilize distinct BCR signaling modes to sustain their proliferation and survival. Constitutive germinal center (GC) BCR signaling in GCB DLBCLs requires the BCR, CD19 and SYK engaging PI(3) kinase for survival. In ABC DLBCLs with oncogenic mutations in the BCR and MYD88, a novel BCR-TLR9-MYD88 signaling supercomplex is assembled on endolysosomal membranes that engages NF-kB. Our data explain why this subset of ABC DLBCL tumors respond frequently to ibrutinib, an inhibitor of BCR-dependent NF- kB activation, while GCB DLBCLs are insensitive, and thus provide a roadmap for the rational development of BCR pathway inhibitors in molecular subtypes of DLBCL. Overall design: Knockdown of TLR9 (C4) was tested in ABC DLBCL cell lines (HBL1 n=2 and TMD8 n=2) for 1 and 2 days. Knockdown of TLR9 (D7) was tested in ABC DLBCL cell lines (HBL1 n=2 and TMD8 n=2) for 1 and 2 days.

INSTRUMENT(S): Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)

SUBMITTER: Louis M. Staudt  

PROVIDER: GSE99276 | GEO | 2018-05-01

REPOSITORIES: GEO

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Publications

A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

Phelan James D JD   Young Ryan M RM   Webster Daniel E DE   Roulland Sandrine S   Wright George W GW   Kasbekar Monica M   Shaffer Arthur L AL   Ceribelli Michele M   Wang James Q JQ   Schmitz Roland R   Nakagawa Masao M   Bachy Emmanuel E   Huang Da Wei DW   Ji Yanlong Y   Chen Lu L   Yang Yandan Y   Zhao Hong H   Yu Xin X   Xu Weihong W   Palisoc Maryknoll M MM   Valadez Racquel R RR   Davies-Hill Theresa T   Wilson Wyndham H WH   Chan Wing C WC   Jaffe Elaine S ES   Gascoyne Randy D RD   Campo Elias E   Rosenwald Andreas A   Ott German G   Delabie Jan J   Rimsza Lisa M LM   Rodriguez Fausto J FJ   Estephan Fayez F   Holdhoff Matthias M   Kruhlak Michael J MJ   Hewitt Stephen M SM   Thomas Craig J CJ   Pittaluga Stefania S   Oellerich Thomas T   Staudt Louis M LM  

Nature 20180620 7718


B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC)2,3, that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade o  ...[more]

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