ArticleThe Journal of clinical investigation2023
Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 41 citations in OpenAlex.
- Expanding the chemical space of Bcl-2 inhibitors: a multiscale computational exploration of the benzopyran (chromene) scaffold.Journal of molecular modeling · 2026Article
- Article
- Spectroscopic Signature of Apoptosis Induced by Venetoclax in Philadelphia-Positive Acute Lymphoblastic Leukemia.Analytical chemistry · 2026Article
- Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.Blood neoplasia · 2026Article
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- CD47 blockade-driven necroptosis complements BCL-2 inhibition-driven apoptosis in lymphoid malignancies.Journal of hematology & oncology · 2026Article
- Bcl-2 inhibitor resistance in diffuse large b-cell lymphoma: establishing a prognostic signature and targeting alpha protein kinase 1.Frontiers in oncology · 2026Article
- Overcoming CAR-T bottlenecks in high-risk DLBCL: a molecular subtyping enhancement strategy.Cancer cell international · 2025Review
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.Leukemia · 2025Article
- Proteasome inhibition overcomes resistance to targeted therapies in B-cell malignancy models and in an index patient.Cell death & disease · 2025Article
- Suppression of NRAS-mutant melanoma growth with NRAS-targeting Antisense Oligonucleotide treatment reveals therapeutically relevant kinase co-dependencies.Communications medicine · 2025Article
- Article
- PRDX1 knockdown promotes erastin-induced ferroptosis and impedes diffuse large B-cell lymphoma development by inhibiting the MAPK/ERK pathway.BMC cancer · 2025Article
- BCL-2 dependence is a favorable predictive marker of response to therapy for chronic lymphocytic leukemia.Molecular cancer · 2025Article
- LAPTM5 Confers the Resistance to Venetoclax via Promoting the Autophagosome-Lysosome Fusion in Multiple Myeloma.Journal of cellular and molecular medicine · 2025Article
- Development of a robust BH3 drug toolkit for precision medicine in hematologic malignancies.Theranostics · 2025Article
- Review
- Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway.Molecular cancer · 2024Article
- Lanthanide conjugate Pr-MPO elicits anti-cancer activity by targeting lysosomal machinery and inducing zinc-dependent cataplerosis.Cell communication and signaling : CCS · 2024Article
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 2 countries.
Funding
Abstract
The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.
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Registered trials
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