title: CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Eriong
authors.initials: E
authors.lastname: Lee-Vergés
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Jocabed
authors.initials: J
authors.lastname: Roldán
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Jiménez
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cabezas
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona and Oncology Program, CIBEREHD, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arimany-Nardí
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona and Oncology Program, CIBEREHD, Barcelona, Spain.
authors.forename: Marçal
authors.initials: M
authors.lastname: Pastor-Anglada
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000069461:Bendamustine Hydrochloride / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010880:Piperidines; D011379:Prognosis; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D000099192:CD69 Antigens
chemical_list: D000225:Adenine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000069461:Bendamustine Hydrochloride; D037181:Lectins, C-Type; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D012333:RNA, Messenger; D000099192:CD69 Antigens; C551803:ibrutinib; C552946:idelalisib
keywords: CD69; bendamustine; chronic lymphocytic leukemia; ibrutinib; idelalisib