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Lymphoma

Existence of reprogrammed lymphoma stem cells in a murine ALCL-like model

Leukemia volume 34, pages 3242–3255 (2020)Cite this article

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Abstract

While cancer stem cells are well established in certain hematologic and solid malignancies, their existence in T cell lymphoma is unclear and the origin of disease is not fully understood. To examine the existence of lymphoma stem cells, we utilized a mouse model of anaplastic large cell lymphoma. Established NPM-ALK+ lymphomas contained heterogeneous cell populations ranging from mature T cells to undifferentiated hematopoietic stem cells. Interestingly, CD4−/CD8− double negative (DN) lymphoma cells aberrantly expressed the T cell receptor α/β chain. Serial transplantation of sorted CD4/CD8 and DN lymphoma subpopulations identified lymphoma stem cells within the DN3/DN4 T cell population, whereas all other subpopulations failed to establish serial lymphomas. Moreover, transplanted lymphoma DN3/DN4 T cells were able to differentiate and gave rise to mature lymphoma T cells. Gene expression analyses unmasked stem-cell-like transcriptional regulation of the identified lymphoma stem cell population. Furthermore, these lymphoma stem cells are characterized by low CD30 expression levels, which might contribute to limited long-term therapeutic success in patients treated with anti-CD30-targeted therapies. In summary, our results highlight the existence of a lymphoma stem cell population in a NPM-ALK-driven CD30+ mouse model, thereby giving the opportunity to test innovative treatment strategies developed to eradicate the origin of disease.

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Fig. 1: ALCL stem cells derive from CD4−/CD8− double negative lymphoma T cells.
Fig. 2: Serially transplanted CD4−/CD8− lymphoma cells differentiate into mature T cells.
Fig. 3: Primary MSNAIE Lck-Cre induced lymphomas contain a heterogeneous cell population ranging from undifferentiated hematopoietic stem cells to mature T cells.
Fig. 4: Lymphoma stem cells reside within the DN3/DN4 T cell population, but not the DN1/DN2 population.
Fig. 5: The gene expression signature of the lymphoma stem cell population reveals a stem-cell-like transcriptional profile.
Fig. 6: The lymphoma stem cell population is characterized by low CD30 expression levels.

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Acknowledgements

We thank Sabina Schaberg for excellent technical assistance. This work was supported by a Grant from the DJCLS (R14/22) and MSCA-ITN-2015-ETN Alkatras to ALI, TP, JD, IG-M, FF, LQ-M and SDT and grants from the DFG to JD (FOR 2033 B1). GA and MB are supported by the DFG within the CRC850. MB is funded by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (DeCaRe, FKZ 01ZX1409B). ALI was supported by a Grant from the Government of Baden-Württemberg (BSL).

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  1. These authors contributed equally: Stefanie Kreutmair, Cathrin Klingeberg

Authors and Affiliations

  1. Department of Medicine I, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany

    Stefanie Kreutmair, Cathrin Klingeberg, Teresa Poggio, Alexander Keller, Cornelius Miething, Marie Follo, Dietmar Pfeifer, Khalid Shoumariyeh, Robert Zeiser, Justus Duyster & Anna L. Illert

  2. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Stefanie Kreutmair, Geoffroy Andrieux, Cornelius Miething, Khalid Shoumariyeh, Robert Zeiser, Melanie Boerries, Justus Duyster & Anna L. Illert

  3. Comprehensive Cancer Center Freiburg (CCCF), University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany

    Stefanie Kreutmair, Alexander Keller, Cornelius Miething, Dietmar Pfeifer, Khalid Shoumariyeh, Robert Zeiser, Melanie Boerries, Justus Duyster & Anna L. Illert

  4. Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany

    Geoffroy Andrieux & Melanie Boerries

  5. Division of Hematology, University Hospital Basel, 4031, Basel, Switzerland

    Claudia Lengerke

  6. Department of Pathology and Neuropathology, University of Tübingen, 72076, Tübingen, Germany

    Irene Gonzalez-Menendez, Falko Fend & Leticia Quintanilla-Martinez

  7. Department of Pathology, University of Cambridge, Cambridge, CB20QQ, UK

    Suzanne D. Turner

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Contributions

SK and CK performed and designed experiments, analysed data and wrote the manuscript. AK, GA, DP, and MB performed and analysed the array data. MF supported flow cytometry and sorting analyses. TP, CM, CL, RZ, SDT, KS, IG-M, FF, and LQ-M provided critical material. JD developed the concept and analysed the data. ALI developed the overall concept, supervised the experiments, analysed data and wrote the manuscript. All Authors edited and reviewed the manuscript.

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Correspondence to Anna L. Illert.

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Kreutmair, S., Klingeberg, C., Poggio, T. et al. Existence of reprogrammed lymphoma stem cells in a murine ALCL-like model. Leukemia 34, 3242–3255 (2020). https://doi.org/10.1038/s41375-020-0789-x

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