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Chronic Lymphocytic Leukemia

Modeling tumor–host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy

Leukemia volume 27, pages 2311–2321 (2013)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, the B-cell receptor (BCR) and nuclear factor- κB (NF-κB) pathways are activated in the lymph node (LN) microenvironment. Thus, model systems mimicking tumor–host interactions are important tools to study CLL biology and pathogenesis. We investigated whether the recently established NOD/scid/γcnull (NSG) mouse xenograft model can recapitulate the effects of the human microenvironment. We assessed, therefore, tumor characteristics previously defined in LN-resident CLL cells, including proliferation, and activation of the BCR and NF-κB pathways. We found that the murine spleen (SP) microenvironment supported CLL cell proliferation and activation to a similar degree than the human LN, including induction of BCR and NF-κB signaling in the xenografted cells. Next, we used this model to study ibrutinib, a Bruton’s tyrosine kinase inhibitor in clinical development. Ibrutinib inhibited BCR and NF-κB signaling induced by the microenvironment, decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, recapitulate the role of the human LN for CLL cells. In addition, we show that ibrutinib effectively disrupts tumor–host interactions essential for CLL cell proliferation and survival in vivo.

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Acknowledgements

We thank Dr Nalini Raghavachari for her assistance setting up the Taqman microfluidics cards, Dr Zu Xi Yu and the NHLBI pathology core for help with slide preparation, and Christina Corsino and the NIAID building 50 animal technicians for their assistance with animal experiments. This research was funded through the Intramural Research Program of the National, Heart, Lung and Blood Institute.

Author contributions

SEMH, XS, EMM and PP-G, planned the research, performed experiments and analyzed data; MMH, KK, CMC, JFT, JC and GA were involved in planning components of the research, contributed reagents and supported experiments; SP and MR provided expert pathology services; DL conducted statistical analyses; JJB was involved in planning components of the research, provided essential reagents, and reviewed the draft manuscript; AW planned and supervised the research, and analyzed data. SEMH, XS, PP-G and AW wrote the paper. All authors approved the final version of the manuscript.

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  1. S E M Herman and X Sun: These authors contributed equally to this work and are co-first authors.

  2. P Pérez-Galán and A Wiestner: These authors contributed equally to this work and are co-senior authors.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    S E M Herman, X Sun, E M McAuley, M M Hsieh, D Liu, K Keyvanfar, C M Chapman, J Chen, G Aue, J F Tisdale & A Wiestner

  2. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S Pittaluga & M Raffeld

  3. Pharmacyclics Inc., Sunnyvale, CA, USA

    J J Buggy

  4. Department of Hemato-Oncology, Institut d’Investigacions Biomédiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain

    P Pérez-Galán

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Correspondence to A Wiestner.

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Competing interests

JJB is an employee of Pharmacyclics Inc. and has financial interest in ibrutinib development. The remaining authors declare no conflict of interest.

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Herman, S., Sun, X., McAuley, E. et al. Modeling tumor–host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia 27, 2311–2321 (2013). https://doi.org/10.1038/leu.2013.131

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