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T-cell acute lymphoblastic leukemia displays autocrine production of Interleukin-7

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by an accumulation of immature T cells. Although patient outcomes have improved, novel targeted therapies are needed to reduce the intensity of chemotherapy and improve the prognosis of high-risk patients. Interleukin-7 (IL-7) modulates the survival and proliferation of normal and malignant T cells. Targeting the IL-7 signaling pathway is thus a potentially effective therapeutic strategy. To achieve such aim, it is essential to first understand how the IL-7 signaling pathway is activated. Although IL-7 production has been observed from multiple stromal tissues, T-ALL autocrine IL-7 secretion has not yet been described. Interestingly, using T-ALL cell lines, primary and patient-derived xenotransplanted (PDX) T-ALL cells, we demonstrate that T-ALL cells produce IL-7 whereas normal T cells do not. Finally, using knock down of IL7 gene in T-ALL cells, we describe to what extent IL-7 autocrine secretion is involved in the T-ALL cells propagation in bone marrow and how it affects the number of leukemia-initiating cells in PDX mice. Together, these results demonstrate how the autocrine production of the IL-7 cytokine mediated by T-ALL cells can be involved in the oncogenic development of T-ALL and offer novel insights into T-ALL spreading.

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  • 01 August 2019

    The original HTML version of this Article was updated after publication because the authors noted that panels D and E had been omitted from Figure 2. The Figure has been updated in the PDF and HTML versions of the article.

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Acknowledgements

The authors express their gratitude to the animal housing facility and cytometry platform staff at the University of Burgundy (Dijon, France), especially Valérie Saint-Giorgio, David Lheraud, Sébastien Lapipe, Anabelle Sequeira, and Serge Monier, for their excellent suggestions and valuable technical support. The authors also thank Julien Guy for providing information on T-ALL immune data that helped in the EGIL characterization, as well as Antonio Vitobello for providing insight about DNA methylation. The authors are also grateful to Suzanne Rankin (CHU Dijon) for editing and proofreading this paper. This study was supported by grants from the Association Laurette Fugain (RQ), the Conférence de Coordination Interrégionale du Grand Est – Bourgogne Franche-Comté (CCIRGE-BFC) de la Ligue contre le Cancer (RQ), by the National Research Agency under the program “Investissements d’Avenir” (reference ANR-11-LABX-0021, LipSTIC Labex), by the Conseil Régional de Bourgogne through the plan d’action régional pour l’innovation (PARI), and the European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs. AB was supported by fellowships from the French Ministère de la Recherche et de l’Enseignement Supérieur (MRES) and the Ligue contre le Cancer. FP and BU have grants from LNCC, INSERM, CEA, and Université Paris Diderot.

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Authors and Affiliations

  1. UMR1231, Inserm/Université Bourgogne Franche-Comté, Dijon, France

    Anne Buffière, Romain Aucagne, François Hermetet, Manon Mas, Sandra Nassurdine, Aziza Aznague, Virginie Carmignac, Jean-Noël Bastie, Laurent Delva & Ronan Quéré

  2. LipSTIC Labex, Dijon, France

    Anne Buffière, Romain Aucagne, François Hermetet, Aziza Aznague, Jean-Noël Bastie, Laurent Delva & Ronan Quéré

  3. UMR967, Inserm/CEA/Université Paris 7/Université Paris 11, Fontenay-aux-Roses, France

    Benjamin Uzan & Françoise Pflumio

  4. LSHL, IRCM/CEA, Fontenay-aux-Roses, France

    Benjamin Uzan & Françoise Pflumio

  5. Hôpital Universitaire François Mitterrand, Service de Génétique des Cancers, Dijon, France

    Benjamin Tournier

  6. Hôpital Universitaire François Mitterrand, Chirurgie Cardiovasculaire, Dijon, France

    Olivier Bouchot

  7. Assistance Publique-Hôpitaux de Paris, Laboratoire d’Hématologie, Hôpital Trousseau, Paris, France

    Paola Ballerini

  8. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    João T. Barata

  9. Hôpital Universitaire François Mitterrand, Service d’Hématologie Clinique, Dijon, France

    Jean-Noël Bastie

  10. Hôpital Universitaire François Mitterrand, CRB Ferdinand Cabanne, BB-0033-00044, Dijon, France

    Jean-Noël Bastie

Authors
  1. Anne Buffière
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  2. Benjamin Uzan
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  10. Olivier Bouchot
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  11. Paola Ballerini
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  12. João T. Barata
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  16. Ronan Quéré
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Contributions

AB and RQ conceived the study, performed experiments, analyzed data, and wrote the paper; BU, RA, FH, MM, SN, AA, VC, and BT helped with experiments; OB provided important material; PB performed cytogenetic; JTB, JNB, and LD discussed the data; FP provided human T-ALL primary samples and xenografts, advices in the usage of such models, discussed the data, and helped with the writing of the paper.

Corresponding author

Correspondence to Ronan Quéré.

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Buffière, A., Uzan, B., Aucagne, R. et al. T-cell acute lymphoblastic leukemia displays autocrine production of Interleukin-7. Oncogene 38, 7357–7365 (2019). https://doi.org/10.1038/s41388-019-0921-4

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