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

Autor: Compagno, Mara, Wang, Qi, Pighi, Chiara, Cheong, Taek-Chin, Meng, Fei-Long, Poggio, Teresa, Yeap, Leng-Siew, Karaca, Elif, Blasco, Rafael B., Langellotto, Fernanda, Ambrogio, Chiara, Voena, Claudia, Wiestner, Adrian, Kasar, Siddha N., Brown, Jennifer R., Sun, Jing, Wu, Catherine J., Gostissa, Monica, Alt, Frederick W., Chiarle, Roberto
Zdroj: Nature; 2/23/2017, Vol. 542 Issue 7642, p489-493, 5p, 14 Graphs
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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