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IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment.

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Affiliations

  • 1. University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
      Authors
    • Leca J 1
    • El Ghamrasni S 1
    • Duncan GS 1
    • Fortin J 1
    • Tobin C 1
    • Hodgson K 1
    • Haight J 1
    • Smith LK 1
    • Elia AJ 1
    • Berger T 1
    (10 authors)
  • 2. University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France; AP-HP, Lymphoid Malignancies Unit, Henri Mondor Hospital, 94010 Créteil, France.
      Authors
    • Lemonnier F 2
    (1 author)
  • 3. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
      Authors
    • Meydan C 3
    • Foox J 3
    (2 authors)
  • 4. University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
      Authors
    • Mboumba DL 4
    (1 author)
  • 5. University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
      Authors
    • Sakamoto T 5
    (1 author)
    • Show all (11)

ORCIDs linked to this article

Cancer Cell, 02 Feb 2023, 41(2):323-339.e10
https://doi.org/10.1016/j.ccell.2023.01.003 PMID: 36736318 

Abstract 

Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Idh2 and Tet2 mutations. Malignant Tfh cells display aberrant transcriptomic and epigenetic programs that impair TCR signaling. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered cross-talk with germinal center B cells that promotes B cell clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. The plasma cell count and angiogenesis are also increased in the Idh2-mutated tumors, implying a major relationship between Idh2 mutation and the characteristic AITL TME. Our mouse model recapitulates several features of human IDH2-mutated AITL and provides a rationale for exploring therapeutic targeting of Tfh-TME cross-talk for AITL patients.

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Read article at publisher's site: https://doi.org/10.1016/j.ccell.2023.01.003

Read article for free, from open access legal sources, via Unpaywall: http://www.cell.com/article/S153561082300003X/pdfUnpaywall

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