Ibrutinib therapy downregulates AID enzyme and proliferative fractions in chronic lymphocytic leukemia.

Blood
Pablo Elías MorandePablo Oppezzo

Abstract

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation and class switch recombination of the immunoglobulin genes. As a trade-off for its physiological function, AID also contributes to tumor development through its mutagenic activity. In chronic lymphocytic leukemia (CLL), AID is overexpressed in the proliferative fractions (PFs) of the malignant B lymphocytes, and its anomalous expression has been associated with a clinical poor outcome. Recent preclinical data suggested that ibrutinib and idelalisib, 2 clinically approved kinase inhibitors, increase AID expression and genomic instability in normal and neoplastic B cells. These results raise concerns about a potential mutagenic risk in patients receiving long-term therapy. To corroborate these findings in the clinical setting, we analyzed AID expression and PFs in a CLL cohort before and during ibrutinib treatment. We found that ibrutinib decreases the CLL PFs and, interestingly, also reduces AID expression, which correlates with dampened AKT and Janus Kinase 1 signaling. Moreover, although ibrutinib increases AID expression in a CLL cell line, it is unable to do so in primary CLL samples. Our results uncover a differential response to ibrutinib between c...Continue Reading

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Citations

Dec 6, 2019·Nature Communications·Guillermo Rodríguez-HernándezArndt Borkhardt
Jul 30, 2020·The New England Journal of Medicine·Jan A Burger
May 11, 2019·Blood·Joseph R Slupsky
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Jun 16, 2021·Nature Reviews. Drug Discovery·Bart VanhaesebroeckKlaus Okkenhaug
Aug 17, 2021·The Cancer Journal·Jan A Burger

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