title: Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia.
abstract: The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation.
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.|Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: L M
authors.initials: LM
authors.lastname: Saleh
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Saba
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Anastas
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Barber
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Corrigan-Cummins
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Farooqui
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.affiliation: Greenwood Genetic Center, Greenwood, SC and School of Nursing, Clemson University, Clemson, SC, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Sarasua
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: N K
authors.initials: NK
authors.lastname: Abousamra
authors.affiliation: Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: O
authors.initials: O
authors.lastname: Elbaz
authors.affiliation: Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: H A
authors.initials: HA
authors.lastname: Abdelghaffar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wiestner
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Calvo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D018941:Antigens, CD19; D015415:Biomarkers; D035683:MicroRNAs; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; C551803:ibrutinib; D000225:Adenine