title: Targeting BTK through microRNA in chronic lymphocytic leukemia.
abstract: Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bottoni
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Lara
authors.initials: L
authors.lastname: Rizzotto
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Tzung-Huei
authors.initials: TH
authors.lastname: Lai
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Chaomei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Rose
authors.initials: R
authors.lastname: Mantel
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Sean
authors.initials: S
authors.lastname: Reiff
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Dalia
authors.initials: D
authors.lastname: El-Gamal
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Karilyn
authors.initials: K
authors.lastname: Larkin
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: James S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors.forename: Deepa
authors.initials: D
authors.lastname: Sampath
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010880:Piperidines; D011401:Promoter Regions, Genetic / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C512352:abexinostat; D000225:Adenine