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Acute Leukemias

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia

Leukemia volume 29, pages 1253–1266 (2015)Cite this article

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Abstract

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN−/− cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN−/−clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

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Acknowledgements

We are sincerely grateful to Ms Cendrine Dubaud regarding her expertise to maintain the mouse strains and assistance to generate the tPTEN−/− KO mice. We also thank the C3M Imaging Core Facility (Microscopy and Imaging Platform Côte d'Azur) and C3M animal room facility. Furthermore, we express thanks to: Ms Chimène Morillon (Affymetrix analysis assistance); Dr Bernard Mari (transcriptomic result discussions) Dr Chloé Féral for discussion about CD98; Dr Marilyne Poirée, Professor Vahid Asnafi and Ms Amélie Trincand for proving primary T-ALL samples and clinical information; Dr Marie Bénéteau (statistical analysis advice); Rodolphe Pontier-Bress (small animal imaging assistance). The Centre Méditerranéen de Médecine Moléculaire (C3M) provided the financial support to perform the current research. CR is a PhD fellowship recipient via La Ligue Nationale Contre le Cancer and EG is supported by a fellowship from La Fondation de France. The Centre Méditerranéen de Médecine Moléculaire (C3M) provided the financial support to perform the current research. BB-M thanks the Benjamin Delessert Institute, AFEF/Aptalis and SFD/MSD for their support.

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Author notes

  1. M Nebout, V Imbert and E Griessinger: These authors contributed equally to this work.

Authors and Affiliations

  1. UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France

    C Rosilio, M Nebout, V Imbert, E Griessinger, Z Neffati, J Benadiba & J-F Peyron

  2. Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France

    C Rosilio, M Nebout, V Imbert, E Griessinger, Z Neffati, J Benadiba & J-F Peyron

  3. Centre Hospitalier Universitaire de Nice, Service d’Oncologie Pédiatrique, Hôpital de l’Archet, Nice, France

    J Benadiba & J-F Peyron

  4. Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA

    T Hagenbeek

  5. Tytgat Institute of Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands

    H Spits

  6. Centre Hospitalier Universitaire de Nice, Laboratoire Central d’Anatomie et Cytologie Pathologiques, Hôpital de l’Archet, Nice, France

    J Reverso, D Ambrosetti & J-F Michiels

  7. INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Complications hépatiques de l’obésité, Nice, France

    B Bailly-Maitre

  8. Department of Pharmacology and Toxicology, Kyorin University, Tokyo, Japan

    H Endou

  9. J-Pharma, Co., Ltd, Yokohama, Japan

    H Endou

  10. Medicinal Chemistry Core Facility, School of Pharmacy, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

    M F Wempe

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  1. C Rosilio
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Correspondence to J-F Peyron.

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Competing interests

HE is CEO of J-Pharma Co., Ltd. (Yokohama, Japan) while MFW served as a Scientific Advisory Board Member for J-Pharma from August 2006 to July 2013. J-Pharma has been developing LAT1 inhibitor JPH203 for use regarding cancer therapeutics/diagnostics; consequently, HE and MFW have a financial interest in J-Pharma. The remaining authors declare no conflict of interest.

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Rosilio, C., Nebout, M., Imbert, V. et al. L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia. Leukemia 29, 1253–1266 (2015). https://doi.org/10.1038/leu.2014.338

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