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 (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM)1. 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 progression2. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells4. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib block PI3Kδ activity directly or indirectly5–8, 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 (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both these effects were 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, but not ibrutinib, 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, an effect that should be carefully considered as such inhibitors are administered for years to patients.

The PI3K Pathway in Human Disease

“…Within the BCR signalosome, BTK and the PI3K p85α/p110δ dimer are required for maximal signaling output as measured by Ca 2+ flux, IκB degradation and Erk phosphorylation. Notably, BTK inhibition can reduce PI3K signaling output in B cells (Bojarczuk et al, 2016; Compagno et al, 2017; Saito et al, 2003), supporting the concept that PI3K and BTK cooperate in the signalosome rather than operating in a simple linear fashion. The functional link between BTK and p85α/p110δ is strongly supported by genetic evidence.…”

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

“…107 However, the combination of ruxolitinib and the pan-PI3K inhibitor buparlisib was relatively disappointing. 108 More recent efforts in this area have focused on drugs that selectively target the d isoform of PI3K 109 ; however, the experience with idelalisib in B-cell malignancies tells a cautionary tale, with reports of induction of genomic instability in B cells 110 and of high rates of immune-mediated hepatotoxicity in previously untreated patients with chronic lymphocytic leukemia. 111 PRM-151 is recombinant human pentraxin-2, a naturally occurring plasma protein also known as serum amyloid P that inhibits fibrocyte differentiation.…”

A targeted treatment with off-target risks

“…The drugs idelalisib and ibrutinib target a B-cell-receptor signalling pathway and are used for cancer treatment; idelalisib and duvelisib (an investigational drug) both inhibit PI3Kδ, and ibrutinib inhibits BTK. Using mouse models and human cells, Compagno et al 2 observed that drug-mediated inhibition of the B-cell-receptor signalling pathway can increase the expression of AID, causing DNA mutations in non-immunoglobulin off-target genespotentially increasing the incidence of tumour-promoting mutations. Effects of drug use are shown in red.…”

“…By contrast, targeted therapies are designed to block specific molecular pathways in cancer cells and induce tumour-cell death without causing DNA damage. On page 489, Compagno et al 2 report studies of mouse models and human cells showing that two targeted drugs that are commonly used instead of chemotherapy in the treatment of certain blood cancers unexpectedly increase DNA damage in both healthy cells and tumour cells.…”

“…Less than a decade ago, extended, planar, fully conjugated polymers were considered to be just a dream 2 . The exciting properties of Liu and colleagues' 2D-CAP open up new horizons in the field of 2D materials and will inspire future efforts in this arena.…”