The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-gamma inducibility of TAP1 and LMP2

Oncogene. 2006 Jul 6;25(29):4016-26. doi: 10.1038/sj.onc.1209434. Epub 2006 Feb 13.

Abstract

The presentation of human leukocyte antigens (HLA) class I requires the coordinated expression of numerous components involved in antigen presentation. Tumor cells may alter the antigen presentation by HLA class I, allowing them to evade antitumor immunity. In many cases, the lack of antigen presentation can be attributed to the downregulation of genes needed for antigen processing, such as the transporters associated with antigen processing (TAP) 1, and the proteasomal component, low molecular weight proteins (LMP) 2. The TAP1 and LMP2 genes are transcribed from a shared bidirectional promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces both TAP1 and LMP2 expression. Low molecular weight proteins2-deficient mice exhibited the development of uterine leiomyosarcomas. Here, the differential responsiveness to IFN-gamma of the SKN human uterine leiomyosarcomas cell line was investigated. We now identify the G871E mutation in the ATP-binding region of Janus kinases 1, suggesting that the loss of TAP1 and LMP2 induction is a defect in the earliest steps of the IFN-gamma-signal pathway, resulting in the inability of SKN cells to upregulate the antigen-processing pathway. Understanding the mechanisms by which these tumors circumvent cytokine signalling, thereby evading antitumor-specific immunity, would greatly aid the efficacy of immunotherapy for treating uterine leiomyosarcomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / immunology
  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / immunology
  • Amino Acid Substitution / genetics
  • Amino Acid Substitution / immunology
  • Animals
  • Antigen Presentation / drug effects
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / immunology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Genes, MHC Class I / immunology
  • HeLa Cells
  • Humans
  • Immunotherapy
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology
  • Janus Kinase 1
  • Leiomyoma / genetics*
  • Leiomyoma / immunology
  • Leiomyoma / therapy
  • Mice
  • Mice, Knockout
  • Point Mutation* / immunology
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Protein Structure, Tertiary / genetics
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / immunology
  • Sarcoma / genetics*
  • Sarcoma / immunology
  • Sarcoma / therapy
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Tumor Escape / drug effects
  • Tumor Escape / genetics*
  • Tumor Escape / immunology
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / immunology
  • Uterine Neoplasms / therapy

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 2
  • ATP-Binding Cassette Transporters
  • Antigens, Neoplasm
  • TAP1 protein, human
  • LMP-2 protein
  • Interferon-gamma
  • Adenosine Triphosphate
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Jak1 protein, mouse
  • Janus Kinase 1
  • Cysteine Endopeptidases