title: FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.
abstract: Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Bouchlaka
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wolff
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Grindle
authors.affiliation: Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Qian
authors.affiliation: Wisconsin Institute for Discovery and Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: N
authors.initials: N
authors.lastname: Pflum
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jobin
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Kahl
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Eickhoff
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Wuerzberger-Davis
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Division of Preclinical Innovation, National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Bethesda, MD, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Yang
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Capitini
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rui
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D044783:F-Box Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D044783:F-Box Proteins; C000595863:FBXO10 protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D013449:Sulfonamides; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D046988:Proteasome Endopeptidase Complex; C579720:venetoclax