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Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients

Oncogene (2018) | Download Citation

Abstract

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

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Acknowledgements

We thank the pediatric patients and donors who provided the clinical samples. This work was supported by the Forschungskredit of the University of Zürich, The Children’s Research Center (CRC) of the Children’s Hospital Zurich, the Stiftung für Krebsbekämpfung and the Krebsliga Schweiz/Swiss Cancer League (grant number KLS 3189-02-2013), the Krebsliga Schweiz/Swiss Cancer League (grant number KLS 3189-02-2013) and the Charles Meyer Cancer Research Initiative.

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  1. These authors contributed equally: Sabrina Traxel, Linda Schadt.

Affiliations

  1. Experimental Infectious Diseases and Cancer Research, Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

    • Sabrina Traxel
    • , Linda Schadt
    • , Tatjana Eyer
    • , Vanessa Mordasini
    • , Felix Niggli
    • , David Nadal
    •  & Simone Bürgler
  2. Division of Otolaryngology, Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

    • Claudine Gysin
  3. KG Jebsen Centre for B Cell Malignancies—Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Ludvig A. Munthe

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The authors declare that they have no conflict of interest.

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Correspondence to Simone Bürgler.

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https://doi.org/10.1038/s41388-018-0594-4