ArticleThe Journal of clinical investigation2019
PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 52 citations in OpenAlex.
- Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.Frontiers in immunology · 2022Pooled it
- A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8Nature metabolism · 2025Article
- Phase Ib study of the oral PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.International journal of clinical oncology · 2025Article
- The potential crosstalk genes and molecular mechanisms between systemic lupus erythematosus and periodontitis.Frontiers in genetics · 2025Article
- Targeting PI3Kδ in cancer: a setback or the end.Frontiers in oncology · 2025Article
- Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting.Frontiers in pharmacology · 2025Review
- PI3K Inhibitors in Hematology: When One Door Closes….Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Molecular cancer · 2023Review
- Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1.Nature communications · 2023Article
- Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors.Blood cancer journal · 2023Article
- Natural Killer Cells in Chronic Lymphocytic Leukemia: Functional Impairment and Therapeutic Potential.Cancers · 2022Review
- Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.Journal of hematology & oncology · 2022Review
- Idelalisib reduces regulatory T cells and activates T helper 17 cell differentiation in relapsed refractory patients with chronic lymphocytic leukaemia.British journal of haematology · 2022Article
- Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies.Frontiers in immunology · 2022Review
- PI3K Targeting in Non-solid Cancer.Current topics in microbiology and immunology · 2022Review
- Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia.Blood advances · 2021Article
- Review
- PI3K inhibitors are finally coming of age.Nature reviews. Drug discovery · 2021Review
- Neutralizing interferon-α blocks inflammation-mediated vascular injury via PI3K and AMPK in systemic lupus erythematosus.Immunology · 2021Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.
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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.