title: CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5-10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Atish
authors.initials: A
authors.lastname: Mohanty
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Sandoval
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Manasi
authors.initials: M
authors.lastname: Das
authors.affiliation: Department of Pathology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Pillai
authors.affiliation: Department of Information Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Chen
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Department of Pathology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lan V
authors.initials: LV
authors.lastname: Pham
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.|Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019938:Cyclin D1; C551803:ibrutinib; D000225:Adenine
keywords: cyclin D1; ibrutinib resistance; mantle cell lymphoma; somatic mutations