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

Pablo Elías Morande, Mariela Sivina, Angimar Uriepero, Noé Seija, Catalina Berca, Pablo Fresia, Ana Inés Landoni, Javier M. Di Noia, Jan A. Burger and Pablo Oppezzo

Key Points

  • AID protein expression and proliferative fractions are decreased during ibrutinib therapy in patients with CLL.

  • Downregulation of AID and proliferative subsets are associated with decrease of AKT and JAK1/STAT6 signaling after ibrutinib therapy.

There is a Blood Commentary on this article in this issue.

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 cell lines and the CLL clone and imply that ibrutinib could differ from idelalisib in their potential to induce AID in treated patients. Possible reasons for the discrepancy between preclinical and clinical findings, and their effect on treatment safety, are discussed.

  • Submitted September 24, 2018.
  • Accepted February 21, 2019.
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