title: Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells.
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.
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Compagno
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pighi
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Taek-Chin
authors.initials: TC
authors.lastname: Cheong
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Fei-Long
authors.initials: FL
authors.lastname: Meng
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Poggio
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Leng-Siew
authors.initials: LS
authors.lastname: Yeap
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Elif
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Blasco
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Langellotto
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Voena
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Siddha N
authors.initials: SN
authors.lastname: Kasar
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology; D052999:Quinazolinones / Q000009:adverse effects / Q000494:pharmacology; D011995:Recombination, Genetic / Q000187:drug effects; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects; D014178:Translocation, Genetic / Q000187:drug effects; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D003564:Cytidine Deaminase; D004791:Enzyme Inhibitors; D007143:Immunoglobulin Heavy Chains; D007546:Isoquinolines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C551803:ibrutinib; C586691:duvelisib; C486018:PIK3CD protein, human; C421683:Pik3cd protein, mouse; C000625951:Btk protein, mouse; C552946:idelalisib