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Cited by 126Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentDNA Repair Mechanisms

Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells

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Compagno, Mara, Wang, Qi, Pighi, Chiara, Cheong, Taek-Chin, Meng, Fei-Long, Poggio, Teresa, Yeap, Leng-Siew, Karaca, Elif +12 more·2017·Nature
DOI 10.1038/nature21406PMC PMC5382874
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Abstract

Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.

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  • There has been no indication that BTKi therapy, in contrast to PI3Kδ inhibition, increases genomic instability in B cells.

    “Further, there has been no indication that BTKi therapy, in contrast to PI3Kδ inhibition, increases genomic instability in B cells (33).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [33]

    The paper reports that the BTK inhibitor ibrutinib increased AID expression and translocation junctions in mouse and human B cells, although less potently than PI3Kδ inhibitors (passage 4, labeled Abstract). It separately reports no increased AID off-target SHM in patients treated with ibrutinib (passage 1, labeled Abstract), but that narrower patient finding does not support the claim that there was no indication of increased genomic instability in B cells. (LLM, conf=0.90)

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Authors
Compagno, M., Wang, Q., Pighi, C., Cheong, T.-C., Meng, F.-L., Poggio, T., Yeap, L.-S., Karaca, E., Blasco, R. B., Langellotto, F., Ambrogio, C., Voena, C., Wiestner, A., Kasar, S. N., Brown, J. R., Sun, J., Wu, C. J., Gostissa, M., Alt, F. W., & Chiarle, R.
Affiliations
  • Boston Children's Hospital (US)
  • University of Turin (IT)
  • Harvard University (US)
  • National Heart, Lung, and Blood Institute (US)
Corresponding author
Chiarle, Roberto
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2017-02
Volume
542
Issue
7642
Pages
489-493
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature21406
PMC
PMC5382874
OpenAlex
W2587810027
Cited by
126
References
3
Citations by year
2026: 6 · 2025: 10 · 2024: 7 · 2023: 7 · 2022: 4 · 2021: 14 · 2020: 14 · 2019: 22 · 2018: 22 · 2017: 20
FWCI
12.25
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Broad Institute
  • Associazione Italiana per la Ricerca sul Cancro (IG-12023)
  • National Institutes of Health
  • National Cancer Institute (U10CA180861, R01CA184922, R01CA216273, R01CA182461, P01CA206978, R01CA196703)
  • National Institute of Allergy and Infectious Diseases (R01AI077595, R37AI077595)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
PI3Kδ inhibitor, activation-induced cytidine deaminase, genomic instability, B cells, idelalisib, duvelisib, ibrutinib, somatic hypermutation, class switch recombination, chromosomal translocation, IGH locus, tumor formation
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Phosphoinositide-3 Kinase Inhibitors, AICDA (Activation-Induced Cytidine Deaminase), Adenine, Animals, Antineoplastic Agents, B-Lymphocytes, Cytidine Deaminase, Enzyme Inhibitors, Female, Humans, Immunoglobulin Heavy Chains, Isoquinolines, Piperidines, Protein-Tyrosine Kinases, Purines, Pyrazoles, Pyrimidines, Recombination, Genetic, Translocation, Genetic, Leukemia, Lymphocytic, Chronic, B-Cell, Immunoglobulin Class Switching, Phosphatidylinositol 3-Kinases, Lymphoma, Mantle-Cell, Somatic Hypermutation, Immunoglobulin, Genomic Instability, Cell Line, Tumor, Mice, Quinazolinones, Class I Phosphatidylinositol 3-Kinases

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