title: Coordinated regulation of the immunoproteasome subunits by PML/RARα and PU.1 in acute promyelocytic leukemia.
abstract: Recognition and elimination of malignant cells by cytotoxic T lymphocytes depends on antigenic peptides generated by proteasomes. It has been established that impairment of the immunoproteasome subunits, that is, PSMB8, PSMB9 and PSMB10 (PSMBs), is critical for malignant cells to escape immune recognition. We report here the regulatory mechanism of the repression of PU.1-dependent activation of PSMBs by PML/RARα in the pathogenesis of acute promyelocytic leukemia (APL) and the unidentified function of all-trans retinoic acid (ATRA) as an immunomodulator in the treatment of APL. Chromatin immunoprecipitation and luciferase reporter assays showed that PU.1 directly bound to and coordinately transactivated the promoters of PSMBs, indicating that PSMBs were transcriptional targets of PU.1 and PU.1 regulated their basal expression. Analysis of expression profiling data from a large population of acute myeloid leukemia (AML) patients revealed that the expression levels of PSMBs were significantly lower in APL patients than in non-APL AML patients. Further evidence demonstrated that the decrease in their expression was achieved through PML/RARα-mediated repression of both PU.1-dependent transactivation and PU.1 expression. Moreover, ATRA but not arsenic trioxide induced the expression of PSMBs in APL cells, indicating that ATRA treatment might activate the antigen-processing/presentation machinery. Finally, the above observations were confirmed in primary APL samples. Collectively, our data demonstrate that PML/RARα suppresses PU.1-dependent activation of the immunosubunits, which may facilitate the escape of APL cells from immune surveillance in leukemia development, and ATRA treatment is able to reactivate their expression, which would promote more efficient T-cell-mediated recognition in the treatment.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: X-W
authors.initials: XW
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: J-Q
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: W-D
authors.initials: WD
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
authors.forename: K-K
authors.initials: KK
authors.lastname: Wang
mesh_terms: D017951:Antigen Presentation; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology; D019139:Tumor Escape; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000077237:Arsenic Trioxide; D001152:Arsenicals; D003546:Cysteine Endopeptidases; D007155:Immunologic Factors; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D025521:Tumor Suppressor Proteins; D000099232:Proto-Oncogene Protein Spi-1; C000607071:RARA protein, human; C070576:PML protein, human; C071313:LMP-2 protein; C077436:LMP7 protein; C098948:PSMB10 protein, human