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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology
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B-Lymphocytes / drug effects*
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B-Lymphocytes / enzymology
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Cell Line, Tumor
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Cytidine Deaminase / metabolism
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacology
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Female
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Genomic Instability / drug effects*
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Humans
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Immunoglobulin Class Switching / drug effects
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Immunoglobulin Heavy Chains / genetics
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Isoquinolines / adverse effects
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Isoquinolines / pharmacology
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / pathology
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Piperidines
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Purines / adverse effects
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Purines / pharmacology
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Pyrazoles / adverse effects
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Pyrazoles / pharmacology
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Pyrimidines / adverse effects
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Pyrimidines / pharmacology
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Quinazolinones / adverse effects
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Quinazolinones / pharmacology
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Recombination, Genetic / drug effects
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Somatic Hypermutation, Immunoglobulin / drug effects
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Translocation, Genetic / drug effects
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Immunoglobulin Heavy Chains
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Isoquinolines
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Phosphoinositide-3 Kinase Inhibitors
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Piperidines
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Purines
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Pyrazoles
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Pyrimidines
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Quinazolinones
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ibrutinib
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duvelisib
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Class I Phosphatidylinositol 3-Kinases
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PIK3CD protein, human
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Pik3cd protein, mouse
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase
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Adenine
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idelalisib