ArticleBlood2023
DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 22 citations in OpenAlex.
- Role of the UHRF1-KLHL6-CORO2B axis in obesity-related insulin resistance.Journal of diabetes investigation · 2026Article
- Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.Nature immunology · 2026Article
- Multimodal ultrasound evaluation of refractory primary thyroid lymphoma: a case report and literature review.Gland surgery · 2026Article
- The ubiquitin ligase KLHL6 drives resistance to CD8Nature · 2026Article
- Mechanisms of first-line treatment resistance in diffuse large B-cell lymphoma.Frontiers in immunology · 2026Review
- Nodal Marginal Zone Lymphoma with Prominent Expansion of PD-1+ T-Follicular Helper Cells: A Persistent Diagnostic Challenge with a Heterogeneous Mutational Architecture.International journal of molecular sciences · 2025Article
- Overcoming CAR-T bottlenecks in high-risk DLBCL: a molecular subtyping enhancement strategy.Cancer cell international · 2025Review
- Decipherment of disulfidptosis-related mutation profile, chemosensitivity, and prognosis in diffuse large B-cell lymphoma.Journal of molecular medicine (Berlin, Germany) · 2025Article
- A novel ubiquitination-based molecular signature predicts prognosis in diffuse large B-cell lymphoma.Annals of hematology · 2025Article
- Advances in lymphoma biomarkers research based on proteomics technology (Review).Oncology reports · 2025Review
- Atypical presentation of secondary hepatic lymphoma with severe hepatic involvement: A case report and literature review.Medicine · 2025Review
- Targeting RPLP2 Triggers DLBCL Ferroptosis by Decreasing FXN Expression.Biomedicines · 2025Article
- ATF6 activation promotes tumorigenesis and drug resistance in diffuse large B-cell lymphoma (DLBCL) by regulating the mTOR/S6K signaling pathway.Discover oncology · 2025Article
- B7-H7 knockdown suppresses the proliferation, metastasis, and drug resistance of B-cell non-Hodgkin lymphoma cells by inhibiting the PI3K/Akt pathway.Frontiers in oncology · 2025Article
- DLD is a potential therapeutic target for COVID-19 infection in diffuse large B-cell lymphoma patients.Apoptosis : an international journal on programmed cell death · 2024Article
- Monomorphic epitheliotropic intestinal T-cell lymphoma: report of four cases and literature review.The Journal of international medical research · 2024Review
- DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.Nature communications · 2024Article
- A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins.ACS chemical biology · 2024Article
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18 authors at 3 institutions in 1 country.
Funding
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.