Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-Cell Lymphoma.

Autor:	Meriranta L; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland., Sorri S; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland., Huse K; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; KG Jebsen Centre for B-cell malignancies and Precision Immunotherapy Alliance, Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Liu X; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Spasevska I; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; KG Jebsen Centre for B-cell malignancies and Precision Immunotherapy Alliance, Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Zafar S; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Chowdhury I; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Dufva O; Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland., Sahlberg E; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Tandarić L; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Karjalainen-Lindsberg ML; Department of Pathology, Helsinki University Hospital, Helsinki, Finland., Hyytiäinen M; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Varjosalo M; Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland., Myklebust JH; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; KG Jebsen Centre for B-cell malignancies and Precision Immunotherapy Alliance, Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Leppä S; Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2024 Sep 03; Vol. 5 (5), pp. 331-352.
DOI:	10.1158/2643-3230.BCD-23-0182
Abstrakt:	Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL) are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin ligase with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiologic KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the bric-a-brac tramtrack broad domain of KLHL6 disrupted its localization and heterodimerization and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL. Significance: Oncogenic BCR signaling sustains DLBCL cells. We discovered that Cullin-3-RING E3 ubiquitin ligase substrate-adapter KLHL6 targets BCR heterodimer (CD79A/CD79B) for ubiquitin-mediated degradation. Recurrent somatic mutations in the KLHL6 gene cause corrupt BCR signaling by disrupting surface BCR homeostasis. Loss of KLHL6 expression and mutant-induced phenotypes associate with targetable disease characteristics in B-cell lymphoma. See related commentary by Leveille et al. See related commentary by Corcoran et al. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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