CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia
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Arnau Montraveta1,*, Eriong Lee-Vergés1,*, Jocabed Roldán1, Laura Jiménez1,3, Sandra Cabezas1,3, Guillem Clot1, Magda Pinyol1, Sílvia Xargay-Torrent1, Laia Rosich1, Cristina Arimany-Nardí2, Marta Aymerich1,3, Neus Villamor1,3, Armando López-Guillermo1,4, Patricia Pérez-Galán1, Gaël Roué1, Marçal Pastor-Anglada2, Elías Campo1,3, Mónica López-Guerra1,3 and Dolors Colomer1,3
1 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2 Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona and Oncology Program, CIBEREHD, Barcelona, Spain
3 Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain
4 Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain
* These authors have contributed equally to the work
Dolors Colomer, email:
Keywords: bendamustine, CD69, ibrutinib, idelalisib, chronic lymphocytic leukemia
Received: September 22, 2015 Accepted: December 12, 2015 Published: December 19, 2015
Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases.
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