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

Oncogene volume 25, pages 4016–4026 (2006)Cite this article

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)-γ-response factor element; thus, the IFN-γ-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-γ 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-γ-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.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

HLA:

human leukocyte antigens

TAP:

transporters associated with antigen processing

LMP:

low molecular weight proteins

IRF-E:

IFN response factor element

IRF-1:

IFN-regulatory factor 1

GAS:

IFN-activated sequence

Jak1:

Janus kinases 1

CTL:

cytotoxic T lymphocyte

STAT1:

signal transducer and activator of transcription 1

NF-κB:

nuclear factor κB

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Acknowledgements

We thank Isamu Ishiwata for his generous gift of the SKN cell lines, and Robert Schreiber for his generous gift of the JAK1−/− MEFs, respectively. We are grateful to Kenneth L Wright for his generous gift of the LMP2 and TAP1 reporter genes, and Jim Ihle for his generous gift of the Jak1 wt expression vectors. We appreciate Dr Toshiaki Saida and the laboratory members of Shinshu University Graduate School of Medicine and Dr S Ferrone, Department of Immunology, Roswell Park Cancer Institute for the critical reading of the manuscript. This work was supported by grants from the Ministry of Education, Culture, Science and Technology, from Kanzawa Medical Research Foundation, and from The Ichiro Kanehara Foundation.

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan

    T Hayashi & S Kohsaka

  2. Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Nagano, Japan

    Y Kobayashi & K Sano

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  1. T Hayashi
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Correspondence to T Hayashi.

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Hayashi, T., Kobayashi, Y., Kohsaka, S. et al. The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-γ inducibility of TAP1 and LMP2. Oncogene 25, 4016–4026 (2006). https://doi.org/10.1038/sj.onc.1209434

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