title: miR-125b and miR-532-3p predict the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients. A French Innovative Leukemia Organization study.
abstract: The underlyingin vivomechanisms of rituximab action remain incompletely understood in chronic lymphocytic leukemia. Recent data suggest that circulating micro-ribonucleic acids correlate with chronic lymphocytic leukemia progression and response to rituximab. Our study aimed at identifying circulating micro-ribonucleic acids that predict response to rituximab monotherapy in chronic lymphocytic leukemia patients. Using a hierarchical clustering of micro-ribonucleic acid expression profiles discriminating 10 untreated patients with low or high lymphocyte counts, we found 26 micro-ribonucleic acids significantly deregulated. Using individual real-time reverse transcription polymerase chain reaction, the expression levels of micro-ribonucleic acids representative of these two clusters were further validated in a larger cohort (n=61). MiR-125b and miR-532-3p were inversely correlated with rituximab-induced lymphodepletion (P=0.020 andP=0.001, respectively) and with the CD20 expression on CD19+cells (P=0.0007 andP<0.0001, respectively).In silicoanalyses of genes putatively targeted by both micro-ribonucleic acids revealed a central role of the interleukin-10 pathway and CD20 (MS4A1) family members. Interestingly, both micro-ribonucleic acids were negatively correlated withMS4A1expression, while they were positively correlated withMS4A3andMSA47Our results identify novel circulating predictive biomarkers for rituximab-mediated lymphodepletion efficacy in chronic lymphocytic leukemia, and suggest a novel molecular mechanism responsible for the rituximab mode of action that bridges miR-125b and miR-532-3p and CD20 family members. (clinicaltrials.gov Identifier: 01370772).
authors.affiliation: CNRS UMR 5235, University of Montpellier, France.|Department of Clinical Hematology, University Hospital Montpellier, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Gagez
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, University Hospital Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duroux-Richard
authors.affiliation: Henri Becquerel Center, Rouen, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Leprêtre
authors.affiliation: Department of Clinical Hematology, Hospital Center of Annecy, Pringy, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Orsini-Piocelle
authors.affiliation: Department of Biological Hematology, APHP, GHUPSSD, Avicenne Hospital, Bobigny, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Letestu
authors.affiliation: Department of Clinical Hematology, Pontchaillou Hospital, Rennes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: De Guibert
authors.affiliation: Department of Bacteriology-Virology, University Hospital Montpellier, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Tuaillon
authors.affiliation: Department of Hematology, La Pitié Salpétrière Hospital, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Leblond
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, University Hospital Montpellier, France.
authors.forename: Olfa
authors.initials: O
authors.lastname: Khalifa
authors.affiliation: CNRS UMR 7292, François Rabelais University, University Hospital Tours, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.affiliation: Department of Hematology, Cote Basque Hospital, Bayonne, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Banos
authors.affiliation: Department of Clinical Hematology, University Hospital Estaing, Clermont-Ferrand, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tournilhac
authors.affiliation: Unit of Lymphoid Hematologic Malignancies, Henri Mondor Hospital, Créteil, France.
authors.forename: Jehan
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, University Hospital Montpellier, France.|Clinical department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: CNRS UMR 5235, University of Montpellier, France g-cartron@chu-montpellier.fr.|Department of Clinical Hematology, University Hospital Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: INSERM, U1183, Institute of Regenerative Medicine and Biotherapy, University Hospital Montpellier, France.|Clinical department for Osteoarticular Diseases, University Hospital Lapeyronie, Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D003937:Diagnosis, Differential; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008212:Lymphocyte Depletion; D008218:Lymphocytosis / Q000175:diagnosis / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D011379:Prognosis; D034622:RNA Interference; D000069283:Rituximab / Q000008:administration & dosage; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C531888:MIRN125 microRNA, human; C585583:MIRN532 microRNA, human; D035683:MicroRNAs; D000069283:Rituximab