Expression of immunoproteasome genes is regulated by cell-intrinsic and –extrinsic factors in human cancers

Based on transcriptomic analyses of thousands of samples from The Cancer Genome Atlas, we report that expression of constitutive proteasome (CP) genes (PSMB5, PSMB6, PSMB7) and immunoproteasome (IP) genes (PSMB8, PSMB9, PSMB10) is increased in most cancer types. In breast cancer, expression of IP genes was determined by the abundance of tumor infiltrating lymphocytes and high expression of IP genes was associated with longer survival. In contrast, IP upregulation in acute myeloid leukemia (AML) was a cell-intrinsic feature that was not associated with longer survival. Expression of IP genes in AML was IFN-independent, correlated with the methylation status of IP genes, and was particularly high in AML with an M5 phenotype and/or MLL rearrangement. Notably, PSMB8 inhibition led to accumulation of polyubiquitinated proteins and cell death in IPhigh but not IPlow AML cells. Co-clustering analysis revealed that genes correlated with IP subunits in non-M5 AMLs were primarily implicated in immune processes. However, in M5 AML, IP genes were primarily co-regulated with genes involved in cell metabolism and proliferation, mitochondrial activity and stress responses. We conclude that M5 AML cells can upregulate IP genes in a cell-intrinsic manner in order to resist cell stress.

[1]  G. Sauvageau,et al.  EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. , 2015, Blood.

[2]  E. Caron,et al.  ER stress affects processing of MHC class I-associated peptides , 2009, BMC Immunology.

[3]  John M. Ashton,et al.  BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. , 2013, Cell stem cell.

[4]  O. Eickelberg,et al.  What shall we do with the damaged proteins in lung disease? Ask the proteasome! , 2012, European Respiratory Journal.

[5]  K. Schwarz,et al.  Immunoproteasomes Largely Replace Constitutive Proteasomes During an Antiviral and Antibacterial Immune Response in the Liver1 , 2001, The Journal of Immunology.

[6]  C. Perreault,et al.  T cells targeted against a single minor histocompatibility antigen can cure solid tumors , 2005, Nature Medicine.

[7]  N. Dantuma,et al.  The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution , 2014, Front. Mol. Neurosci..

[8]  P. Kaiser,et al.  Protein degradation and the stress response. , 2012, Seminars in cell & developmental biology.

[9]  J. Dick,et al.  AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress. , 2015, Blood.

[10]  M. Lako,et al.  A Putative Role for the Immunoproteasome in the Maintenance of Pluripotency in Human Embryonic Stem Cells , 2012, Stem cells.

[11]  G. Willimsky,et al.  The adaptive immune response to sporadic cancer , 2007, Immunological reviews.

[12]  P. Pandolfi,et al.  Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia , 2013, The Journal of experimental medicine.

[13]  G. Boucher,et al.  The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias , 2015, Nature Genetics.

[14]  Benjamin J. Raphael,et al.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. , 2013, The New England journal of medicine.

[15]  M. Groettrup,et al.  The immunoproteasome in antigen processing and other immunological functions. , 2013, Current opinion in immunology.

[16]  Parantu K. Shah,et al.  Transcription factor-pathway co-expression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma , 2013, Leukemia.

[17]  T. Schumacher,et al.  Acquired and intrinsic resistance in cancer immunotherapy , 2014, Molecular oncology.

[18]  G. Kroemer,et al.  Prognostic and predictive impact of intra- and peritumoral immune infiltrates. , 2011, Cancer research.

[19]  J. Taylor,et al.  Selective Accumulation of Aggregation-Prone Proteasome Substrates in Response to Proteotoxic Stress , 2009, Molecular and Cellular Biology.

[20]  L. Jouneau,et al.  The Proto-MHC of Placozoans, a Region Specialized in Cellular Stress and Ubiquitination/Proteasome Pathways , 2014, The Journal of Immunology.

[21]  N. Villamor,et al.  Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells , 2003, Leukemia.

[22]  R. Mallampalli,et al.  Emerging therapies targeting the ubiquitin proteasome system in cancer. , 2014, The Journal of clinical investigation.

[23]  Wooin Lee,et al.  The immunoproteasome as a therapeutic target for hematological malignancies. , 2014, Current Cancer Drug Targets.

[24]  Mark Gerstein,et al.  OrthoClust: an orthology-based network framework for clustering data across multiple species , 2014, Genome Biology.

[25]  H. Rammensee,et al.  Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products , 2001, The Journal of experimental medicine.

[26]  Matko Bosnjak,et al.  REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms , 2011, PloS one.

[27]  H. Overkleeft,et al.  Structure-based design of beta 1i or beta 5i specific inhibitors of human immunoproteasomes , 2014 .

[28]  Sébastien Lemieux,et al.  Deletion of Immunoproteasome Subunits Imprints on the Transcriptome and Has a Broad Impact on Peptides Presented by Major Histocompatibility Complex I molecules* , 2010, Molecular & Cellular Proteomics.

[29]  Margaret A. Goodell,et al.  DNMT3A in haematological malignancies , 2015, Nature Reviews Cancer.

[30]  J. Christman,et al.  5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy , 2002, Oncogene.

[31]  P. Kloetzel,et al.  IFN-gamma-induced immune adaptation of the proteasome system is an accelerated and transient response. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[33]  Thomas D. Wu,et al.  A comprehensive transcriptional portrait of human cancer cell lines , 2014, Nature Biotechnology.

[34]  H. Overkleeft,et al.  Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes. , 2014, Journal of medicinal chemistry.

[35]  B. J. Van den Eynde,et al.  Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules , 2010, Proceedings of the National Academy of Sciences.

[36]  R. Kaufman,et al.  The impact of the unfolded protein response on human disease , 2012, The Journal of cell biology.

[37]  Michael R. Speicher,et al.  The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis , 2016, Science Translational Medicine.

[38]  Hermann-Georg Holzhütter,et al.  Modeling the in vitro 20S proteasome activity: the effect of PA28-alphabeta and of the sequence and length of polypeptides on the degradation kinetics. , 2008, Journal of molecular biology.

[39]  S. Baylin,et al.  DNA methylation and gene silencing in cancer , 2005, Nature Clinical Practice Oncology.

[40]  B. J. Van den Eynde,et al.  This information is current as Proteasomes Tumor Antigens by Intermediate Analysis of the Processing of Seven Human Parmentier , 2012 .

[41]  B. Moore,et al.  Molecular mechanisms of acquired proteasome inhibitor resistance. , 2012, Journal of medicinal chemistry.

[42]  Z. Trajanoski,et al.  Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability. , 2016, Immunity.

[43]  C. Ruppert,et al.  Regulation of Immunoproteasome Function in the Lung , 2015, Scientific Reports.

[44]  B. Kuster,et al.  Mass-spectrometry-based draft of the human proteome , 2014, Nature.

[45]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[46]  T. Muchamuel,et al.  Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis , 2014, EMBO molecular medicine.

[47]  C. Reilly,et al.  Transformation of the proteasome with age‐related macular degeneration , 2007, FEBS letters.

[48]  Khalid W. Kalim,et al.  A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis , 2009, Nature Medicine.

[49]  Assya Trofimov,et al.  Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells , 2014, The Journal of Immunology.

[50]  N. Hay,et al.  Molecular Pathways: Reactive Oxygen Species Homeostasis in Cancer Cells and Implications for Cancer Therapy , 2013, Clinical Cancer Research.

[51]  C. Cheroni,et al.  Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response , 2012, Progress in Neurobiology.

[52]  R. deLeeuw,et al.  Tumor-Infiltrating Lymphocytes Expressing the Tissue Resident Memory Marker CD103 Are Associated with Increased Survival in High-Grade Serous Ovarian Cancer , 2013, Clinical Cancer Research.

[53]  Ted G. Graber,et al.  Immunoproteasome in animal models of Duchenne muscular dystrophy , 2014, Journal of Muscle Research and Cell Motility.