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

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.

• Authors: Pablo Elías Morande, Mariela Sivina, Angimar Uriepero, Noé Seija, Catalina Berca, Pablo Fresia, Ana Inés Landoni, Javier M Di Noia, Jan A Burger, Pablo Oppezzo
• Journal: Blood (Blood) Vol. 133 Issue 19 Pg. 2056-2068 (05 09 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30814061 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents, Immunological
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• AICDA (activation-induced cytidine deaminase)
• Cytidine Deaminase
• Adenine

Topics

• Adenine (analogs & derivatives)
• Aged
• Antineoplastic Agents, Immunological (adverse effects)
• Cell Proliferation (drug effects)
• Cytidine Deaminase (biosynthesis, drug effects)
• Down-Regulation
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Male
• Middle Aged
• Piperidines
• Pyrazoles (adverse effects)
• Pyrimidines (adverse effects)