Genomics

Dataset Information

166

Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells


ABSTRACT: Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM). Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib inhibit PI3Kδ activity directly or indirectly through inhibition of the Bruton tyrosine kinase (BTK), thus possibly 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 (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. These effects were both completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. Since such inhibitors are administered for years to patients, their genotoxic potential should be carefully considered while planning therapeutic protocols. Overall design: We applied a genome-wide translocation technique we previously developed (High-Throughput Genomic Translocation Sequencing approach, HTGTS) to identify translocation partners from DNA double strand breaks (DSBs) introduced into the c-myc locus (Chiarle et al, Cell 2011) in Mouse and Human B cell treated with PI3K inhibitors. We also re-sequenced selected mouse and human genomic regions from template DNA for somatic hypermutation (SHM) analysis in samples treated with PI3K delta inhibitors. We also performed GRO-Seq experiments in activated B cells treated with PI3K delta inhibitors to find correlations between transcription and translocation junction frequency.

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Roberto Chiarle  

PROVIDER: GSE77788 | GEO | 2017-01-31

SECONDARY ACCESSION(S): PRJNA311552

REPOSITORIES: GEO

altmetric image

Publications


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  ...[more]

Similar Datasets

2007-11-01 | GSE9249 | GEO
2015-12-08 | E-GEOD-48304 | ArrayExpress
| GSE92430 | GEO
| GSE62296 | GEO
2014-12-04 | E-GEOD-62296 | ArrayExpress
2011-01-21 | GSE24827 | GEO
2011-01-21 | E-GEOD-24827 | ArrayExpress
2016-02-21 | E-GEOD-77141 | ArrayExpress
| PRJNA310286 | ENA
| GSE89869 | GEO