title: The novel function of CD82 and its impact on BCL2L12 via AKT/STAT5 signal pathway in acute myelogenous leukemia cells.
abstract: The aim of this study was to explore the biological functions of a tetraspanin family protein CD82 expressed aberrantly in chemotherapy-resistant CD34(+)/CD38(-) acute myelogenous leukemia (AML) cells. Microarray analysis of patient-isolated CD34(+)/CD38(-) AML cells revealed that the levels of anti-apoptotic protein BCL2L12 were downregulated after CD82 depletion by specific short hairpin RNA (shRNA). Western blot analysis indicated that BCL2L12 was aberrantly expressed in patient-isolated AML cells and AML cell lines. Furthermore, CD82 blockade by a specific antibody downregulated BCL2L12 in parallel with dephosphorylation of signal transducer and activator of transcription 5 (STAT5) and AKT, whereas pharmacological inhibition of STAT5 and AKT activation decreased BCL2L12 expression in leukemia cells. In addition, shRNA-mediated downregulation of BCL2L12 increased the levels of cleaved caspase-3 and suppressed proliferation of leukemia cells, impairing their engraftment in immunodeficient mice. Taken together, our results indicate that CD82 regulated BCL2L12 expression via STAT5A and AKT signaling and stimulated proliferation and engrafting of leukemia cells, suggesting that CD82 and BCL2L12 may be promising therapeutic targets in AML.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Nishioka
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: The Facility for Animal Research, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nobumoto
authors.affiliation: The Facility for Animal Research, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D005260:Female; D006801:Humans; D051861:Kangai-1 Protein / Q000032:analysis / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000032:analysis / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome
chemical_list: C430100:BCL2L12 protein, human; C497688:CD82 protein, human; D051861:Kangai-1 Protein; D009124:Muscle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt