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  3. Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets

Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets

  • Nat Commun. 2024 Oct 22;15(1):9106. doi: 10.1038/s41467-024-53376-1.
Junji Koya # 1 2,  Tomohiko Tanigawa # 1 2,  Kota Mizuno 1 2,  Haryoon Kim 1 2,  Yuta Ito 1 3,  Mitsuhiro Yuasa 1 4,  Kentaro Yamaguchi 1 2,  Yasunori Kogure 1,  Yuki Saito 1 5,  Sumito Shingaki 1,  Mariko Tabata 1 6,  Koichi Murakami 1 2,  Kenichi Chiba 7,  Ai Okada 7,  Yuichi Shiraishi 7,  Amira Marouf 8,  Raphaël Liévin 8,  Sammara Chaubard 9,  Arnaud Jaccard 9,  Olivier Hermine 8 10,  Laurence de Leval 11,  Olivier Tournilhac 12,  Gandhi Damaj 13,  Philippe Gaulard 14 15,  Lucile Couronné 8 16,  Teruhito Yasui 17 18,  Kazutaka Nakashima 19,  Hiroaki Miyoshi 19,  Koichi Ohshima 19,  Keisuke Kataoka 20 21
Affiliations

Affiliations

  • 1 Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
  • 2 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • 3 Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
  • 4 Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 5 Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
  • 6 Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 7 Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
  • 8 Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM UMR_S 1163, Imagine Institute, Université Paris Cité, Paris, France.
  • 9 Hematology department, Limoges University Hospital, Limoges, France.
  • 10 Hematology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
  • 11 Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
  • 12 Department of Hematology, Clermont-Ferrand University Hospital, Clermont Auvergne University, Clermont-Ferrand, France.
  • 13 Department of Hematology, Caen University Hospital, Normandy University, Caen, France.
  • 14 University Paris Est Créteil, INSERMU955, IMRB, Créteil, France.
  • 15 Pathology Department, Henri Mondor University Hospital, Assistance Publique -Hôpitaux de Paris (APHP), Créteil, France.
  • 16 Laboratory of Onco-Hematology, Necker Children's Hospital, Assistance Publique -Hôpitaux de Paris (APHP), Paris, France.
  • 17 Laboratory of Infectious Diseases and Immunity, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki City, Japan.
  • 18 Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
  • 19 Division of Pathology, Kurume University, Fukuoka, Japan.
  • 20 Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
  • 21 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. kkataoka-tky@umin.ac.jp.
  • # Contributed equally.
PMID: 39438472 DOI: 10.1038/s41467-024-53376-1
Abstract

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 Inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies.

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