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Animal Models

Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML

Leukemia volume 26, pages 1030–1037 (2012)Cite this article

Abstract

Spleen size ranks among the most important risk factors in chronic myeloid leukemia (CML), but the pathogenic mechanisms of splenic hematopoiesis in CML remain poorly defined. Here, we studied the biology of Bcr–Abl positive leukemia-initiating cells in the spleen, using an inducible transgenic mouse model of CML. Disease kinetics showed greater increases of immature leukemic cells in spleen vs bone marrow (BM). To assess how Bcr–Abl alters the behavior of spleen-derived CML cells, we transplanted these cells either before (‘pre-uninduced’) or 44 days after (‘pre-induced’) expression of the oncogene. Mice transplanted with pre-induced spleen cells showed significantly increased neutrophilia and splenomegaly compared with mice receiving pre-uninduced spleen cells, suggesting that Bcr–Abl expression in the donors had increased splenic tumor burden. However, pre-induction also altered the biology of these cells, as shown by a striking increase in erythropoietic potential. These results differ from those of BM-derived CML stem cells where pre-induction of Bcr–Abl had previously been shown to decrease disease transplantability. Moreover, splenic cells were less sensitive to imatinib than BM cells. In conclusion, Bcr–Abl alters the biology of splenic leukemic stem cells by a cell-autonomous mechanism, but the disease phenotype is also influenced by the microenvironment of these cells.

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Acknowledgements

This work was supported by grants from the German Research Foundation (DFG Kos 2155/2-2) and Innovative Forschung Münster (IMF KO 1 2 08 19).

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Authors and Affiliations

  1. Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany

    M Schemionek, L Kerstiens, C Elling, W E Berdel, C Müller-Tidow & S Koschmieder

  2. Department of Pathology, University of Münster, Münster, Germany

    T Spieker

  3. Division of Stem Cells and Cancer, HI-STEM (Heidelberg Institute for Stem Cell Technology and Experimental Medicine), German Cancer Research Center (DKFZ), Heidelberg, Germany

    M Essers & A Trumpp

  4. Department of Medicine IV/Oncology, Hematology, and Stem Cell Transplant, University of Aachen, Aachen, Germany

    S Koschmieder

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  1. M Schemionek
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Correspondence to S Koschmieder.

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Competing interests

SK has received research support from Novartis (however, not for the research described here) and has served on advisory boards of Novartis and Bristol Myers Squibb.

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Schemionek, M., Spieker, T., Kerstiens, L. et al. Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML. Leukemia 26, 1030–1037 (2012). https://doi.org/10.1038/leu.2011.366

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