Chronic Lymphocytic Leukemia Coverage from Every Angle
Advertisement
Advertisement

Does UGT2B17 Alter Treatment Response in CLL?

By: Kayci Reyer
Posted: Tuesday, July 14, 2020

According to research published in the British Journal of Cancer, the lymphoid glucuronosyltransferase UGT2B17 may result in reduced treatment sensitivity in patients with chronic lymphocytic leukemia (CLL). This response modification appears to occur via direct inactivation.

“The impact of glucuronidation in the inactivation of a number of antileukemic drugs is underestimated, since we established that most agents are subjected to this metabolic process, including ibrutinib, idelalisib, venetoclax, and duvelisib as well as other small molecules under development such as acalabrutinib and cerdulatinib,” concluded Chantal Guillemette, PhD, of the Centre Hospitalier Universitaire de Québec, Canada, and colleagues.

The study included 20 patients who were diagnosed with CLL between 1987 and 2011. Prior to and after an initial fludarabine-containing treatment cycle, a UGT2B17 mRNA analysis was performed on CD19-positive–sorted cells. In the first week following treatment, 2 patients treated with fludarabine/chlorambucil/rituximab and 15 patients treated with ibrutinib had samples for quantification of glucuronides in circulation available. Mass spectrometry was used to analyze the cryopreserved peripheral blood mononuclear cells and plasma samples from these patients, whereas cytotoxicity assays and RNA sequencing were used to evaluate treatment response and transcriptome changes in patients with high UGT2B17 levels.

B-cell models with high UGT2B17 experienced a decreased sensitivity to fludarabine, ibrutinib, and idelalisib. Short-term treatment with these three agents induced UGT2B17 expression in leukemic cells. Patients receiving either fludarabine or ibrutinib had detectable glucuronides, but UGT2B17 conjugated fludarabine alone but not ibrutinib. In patients treated with fludarabine and in fludarabine-treated cell models, AMP-activated protein kinase was associated with high levels of UGT2B17. Through UGT2B17-related expression changes, nuclear factor kappa B was revealed to be a key regulatory hub.

Disclosure: The study authors reported no conflicts of interest.



By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.