title: SUMOylation Confers Posttranslational Stability on NPM-ALK Oncogenic Protein.
abstract: Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+) T-cell lymphoma is an aggressive form of cancer that commonly affects children and adolescents. The expression of NPM-ALK chimeric oncogene results from the chromosomal translocation t(2;5)(p23;q35) that causes the fusion of the ALK and NPM genes. This translocation generates the NPM-ALK protein tyrosine kinase that forms the constitutively activated NPM-ALK/NPM-ALK homodimers. In addition, NPM-ALK is structurally associated with wild-type NPM to form NPM/NPM-ALK heterodimers, which can translocate to the nucleus. The mechanisms that sustain the stability of NPM-ALK are not fully understood. SUMOylation is a posttranslational modification that is characterized by the reversible conjugation of small ubiquitin-like modifiers (SUMOs) with target proteins. SUMO competes with ubiquitin for substrate binding and therefore, SUMOylation is believed to protect target proteins from proteasomal degradation. Moreover, SUMOylation contributes to the subcellular distribution of target proteins. Herein, we found that the SUMOylation pathway is deregulated in NPM-ALK+ T-cell lymphoma cell lines and primary lymphoma tumors from patients. We also identified Lys24 and Lys32 within the NPM domain as the sites where NPM-ALK conjugates with SUMO-1 and SUMO-3. Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation. One possible mechanism for the SENP1-mediated decrease in NPM-ALK levels was the increase in NPM-ALK association with ubiquitin, which facilitates its degradation. Our findings propose a model in which aberrancies in SUMOylation contribute to the pathogenesis of NPM-ALK+ T-cell lymphoma. Unraveling such pathogenic mechanisms may lead to devising novel strategies to eliminate this aggressive neoplasm.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: dtvishwa@mdanderson.org.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Vishwamitra
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
authors.forename: Choladda V
authors.initials: CV
authors.lastname: Curry
authors.affiliation: State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Serhan
authors.initials: S
authors.lastname: Alkan
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences, Houston, TX. Electronic address: hamin@mdanderson.org.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
mesh_terms: D006801:Humans; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000502:physiology*
chemical_list: D015514:Oncogene Proteins, Fusion; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases