KLHL6 is a tumor suppressor gene in diffuse large B-cell lymphoma

Choi, Jaewoo; Zhou, Nan; Busino, Luca

doi:10.1080/15384101.2019.1568765

Cited by 11 publications

(8 citation statements)

References 56 publications

(81 reference statements)

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“…As previously reported in other lymphoma subtypes, in 86% (6/7) of PBL cases with identified KLHL6 mutations the mutations clustered in the hotspot domain BTB, possibly leading to a dissociation of KLHL6 and cullin3 that form a functional cullin-RING ubiquitin ligase. KLHL6 mutations have been described to disrupt this ligase function and to contribute to the growth of diffuse large B-cell lymphoma (DLBCL) cells in vitro and in vivo [11][12][13] .…”

Section: Resultsmentioning

confidence: 99%

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

et al. 2021

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Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

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Section: Resultsmentioning

confidence: 99%

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

et al. 2021

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“…The number of mutated regions associated with SBS9 was high compared to other signatures, and interestingly, a missense mutation for KLHL6 was identified in the gene set corresponding to SBS9; thus, we could hypothesize that the etiology of SBS9, probably AID or polymerase eta, might be associated with KLHL6. Recent studies suggest that KLHL6 may be an essential tumor suppressor gene in B-cell lymphoma [26, 27]. Therefore, KLHL6 aberration may lead to high activity of the mutational process of SBS9, resulting in a large number of somatic mutations.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies suggest that KLHL6 may be an essential tumor suppressor gene in B-cell lymphoma [26,27]. Therefore, KLHL6 aberration may lead to high activity of the mutational process of SBS9, resulting in a large number of somatic mutations.…”

Section: Somatic Mutations Strongly Associated With Each Signaturementioning

confidence: 99%

Clone decomposition based on mutation signatures provides novel insights into mutational processes

Matsutani

Hamada

2021

Preprint

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Intra-tumor heterogeneity is a phenomenon in which mutation profiles differ from cell to cell within the same tumor and is observed in almost all tumors. Understanding intra-tumor heterogeneity is essential from the clinical perspective. Numerous methods have been developed to predict this phenomenon based on variant allele frequency. Among the methods, CloneSig models the variant allele frequency and mutation signatures simultaneously and provides an accurate clone decomposition. However, this method has limitations in terms of clone number selection and modeling. We propose SigTracer, a novel hierarchical Bayesian approach for analyzing intra-tumor heterogeneity based on mutation signatures to tackle these issues. We show that SigTracer predicts more reasonable clone decompositions than the existing methods that use artificial data that mimic cancer genomes. We applied SigTracer to whole-genome sequences of blood cancer samples. The results were consistent with past findings that single base substitutions caused by a specific signature (previously reported as SBS9) related to the activation-induced cytidine deaminase intensively lie within immunoglobulin-coding regions for chronic lymphocytic leukemia samples. Furthermore, we showed that this signature mutates regions responsible for cell-cell adhesion. Accurate assignments of mutations to signatures by SigTracer can provide novel insights into signature origins and mutational processes.

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“…The number of mutated regions associated with SBS9 was high compared to other signatures, and interestingly, a missense mutation for KLHL6 was identified in the gene set corresponding to SBS9; thus, we could hypothesize that the etiology of SBS9, probably AID or polymerase eta, might be associated with KLHL6. Recent studies suggest that KLHL6 may be an essential tumor suppressor gene in B-cell lymphoma ( 29 , 30 ). Therefore, KLHL6 aberration may lead to high activity of the mutational process of SBS9, resulting in a large number of somatic mutations.…”

Section: Resultsmentioning

confidence: 99%

Clone decomposition based on mutation signatures provides novel insights into mutational processes

Matsutani

Hamada

2021

NAR Genomics and Bioinformatics

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Intra-tumor heterogeneity is a phenomenon in which mutation profiles differ from cell to cell within the same tumor and is observed in almost all tumors. Understanding intra-tumor heterogeneity is essential from the clinical perspective. Numerous methods have been developed to predict this phenomenon based on variant allele frequency. Among the methods, CloneSig models the variant allele frequency and mutation signatures simultaneously and provides an accurate clone decomposition. However, this method has limitations in terms of clone number selection and modeling. We propose SigTracer, a novel hierarchical Bayesian approach for analyzing intra-tumor heterogeneity based on mutation signatures to tackle these issues. We show that SigTracer predicts more reasonable clone decompositions than the existing methods against artificial data that mimic cancer genomes. We applied SigTracer to whole-genome sequences of blood cancer samples. The results were consistent with past findings that single base substitutions caused by a specific signature (previously reported as SBS9) related to the activation-induced cytidine deaminase intensively lie within immunoglobulin-coding regions for chronic lymphocytic leukemia samples. Furthermore, we showed that this signature mutates regions responsible for cell–cell adhesion. Accurate assignments of mutations to signatures by SigTracer can provide novel insights into signature origins and mutational processes.

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KLHL6 is a tumor suppressor gene in diffuse large B-cell lymphoma

Cited by 11 publications

References 56 publications

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Clone decomposition based on mutation signatures provides novel insights into mutational processes

Clone decomposition based on mutation signatures provides novel insights into mutational processes

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