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DOI | 10.1002/2016JD025581 |
Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells | |
Compagno, Mara1,2; Wang, Qi1,2; Pighi, Chiara1,2; Cheong, Taek-Chin1,2; Meng, Fei-Long3,4,8; Poggio, Teresa5; Yeap, Leng-Siew3,4,9; Karaca, Elif1,2; Blasco, Rafael B.1,2; Langellotto, Fernanda1,2,10; Ambrogio, Chiara; Voena, Claudia1,2,5; Wiestner, Adrian7; Kasar, Siddha N.6; Brown, Jennifer R. .6; Sun, Jing6; Wu, Catherine J.; Gostissa, Monica3,4,10; Alt, Frederick W.3,4; Chiarle, Roberto1,2,5 | |
2017-02-23 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2017 |
卷号 | 542期号:7642页码:489-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Italy; Peoples R China |
英文摘要 | Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation(1). 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(2). AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase delta (PI3K delta) pathway regulates AID by suppressing its expression in B cells4. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3K delta activity directly or indirectly(5-8), 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. PI3K delta inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3K delta 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 PI3K delta 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000395094100039 |
WOS关键词 | INDUCED CYTIDINE DEAMINASE ; CLASS-SWITCH RECOMBINATION ; SEQUENCING REVEALS ; SUPER-ENHANCERS ; TARGETING BTK ; AID ; DNA ; TRANSCRIPTION ; MECHANISMS ; IBRUTINIB |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/33423 |
专题 | 气候变化 |
作者单位 | 1.Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA; 2.Harvard Med Sch, Boston, MA 02115 USA; 3.Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA; 4.Harvard Med Sch, Dept Genet, Boston, MA 02115 USA; 5.Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy; 6.Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA; 7.Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA; 8.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China; 9.Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China; 10.Agenus Inc, 3 Forbes Rd, Lexington, MA 02421 USA |
推荐引用方式 GB/T 7714 | Compagno, Mara,Wang, Qi,Pighi, Chiara,et al. Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells[J]. NATURE,2017,542(7642):489-+. |
APA | Compagno, Mara.,Wang, Qi.,Pighi, Chiara.,Cheong, Taek-Chin.,Meng, Fei-Long.,...&Chiarle, Roberto.(2017).Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells.NATURE,542(7642),489-+. |
MLA | Compagno, Mara,et al."Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells".NATURE 542.7642(2017):489-+. |
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