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Series GSE77788 Query DataSets for GSE77788
Status Public on Jan 31, 2017
Title Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells
Organisms Homo sapiens; Mus musculus
Experiment type Other
Expression profiling by high throughput sequencing
Summary 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.
Contributor(s) Compagno M, Wang Q, Chiarle R
Citation(s) 28199309
Submission date Feb 10, 2016
Last update date May 15, 2019
Contact name Roberto Chiarle
Organization name Children’s Hospital Boston and Harvard Medical School
Department Department of Pathology
Lab Roberto Chiarle
Street address 300 Longwood Avenue
City Boston
State/province Massachusetts
ZIP/Postal code 02115
Country USA
Platforms (3)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL15520 Illumina MiSeq (Homo sapiens)
GPL16417 Illumina MiSeq (Mus musculus)
Samples (162)
GSM2059291 HTGTS_DMSO rep1
GSM2059292 HTGTS_DMSO rep2
GSM2059293 HTGTS_DMSO rep3
BioProject PRJNA311552
SRA SRP069868

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Supplementary file Size Download File type/resource
GSE77788_RAW.tar 24.5 Mb (http)(custom) TAR (of BED, TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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