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Stem cell biology

PIM1 inhibition effectively enhances plerixafor-induced HSC mobilization by counteracting CXCR4 upregulation and blocking CXCL12 secretion

Leukemia volume 33, pages 1296–1301 (2019)Cite this article

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Hematopoietic stem cell (HSC) collection is essential for autologous and allogeneic bone marrow (BM) transplantation, and requires the mobilization of HSCs from the BM niche into the peripheral blood (PB). Therefore, it is necessary to interrupt adhesion and signaling processes in between HSCs and niche cells that retain HSCs in the BM. The interplay is best described for the C-X-C chemokine motif receptor 4 (CXCR4) and its ligand, stromal cell-derived factor 1α (SDF-1α/CXCL12). HSCs express CXCR4, and are chemo-attracted to and retained within the BM by CXCL12 [1,2,3,4]. SDF-1α is mainly produced by CXCL12-abundant reticular (CAR) cells [5], and by nestin-positive mesenchymal stem cells (MSCs) [6]. Genetic deletion of either Cxcr4 or Cxcl12 in mice is perinatally lethal, with a failure of HSCs to traffic to the BM niche during development. Therefore, CXCR4 antagonists like AMD3100/plerixafor are used in the clinic for the collection of HSCs from patients who fail to mobilize HSCs in response to granulocyte-colony stimulating factor (G-CSF) [7,8,9]; however, their effects are short-lived, limiting the collection time to only 4–6 h. In addition, about 30% of the patients treated with plerixafor after G-CSF failure do not achieve the required amounts of CD34+ cells for autologous transplantation. We have previously demonstrated that the PIM1 (Proviral integration site for Moloney murine leukemia virus) kinase regulates CXCR4 receptor recycling and surface expression on HSCs [10, 11]. Consequently, deletion of Pim1 results in reduced CXCR4 expression of HSCs, reduced migration of HSCs toward a CXCL12 gradient, and reduced homing to the BM [11].

Next, we asked whether Pim1 deficiency could counteract the upregulation of the CXCR4 receptor after plerixafor treatment, and would allow for improved HSC mobilization. Pim1−/− and wild-type (WT) control mice were treated with plerixafor and the LSK frequency in the PB was measured using flow cytometry (staining protocol in Figure S1). As described before [8], the highest number of PB-LSKs was measured 1 h after injection of plerixafor. Pim1-deficient mice showed a significantly and strongly improved HSC mobilization with around 2 × 103 LSK cells/ml PB compared to 1 × 103 LSK cells/ml PB in WT animals. LSK mobilization in Pim1−/− mice was also prolonged from 4 to around 12 h post plerixafor injection (Fig. 1c). Besides LSKs, also other Sca-1+ cells were increasingly mobilized in Pim1−/− mice (Fig. 1d), whereas myeloid progenitor mobilization of c-Kit+ Sca-1− cells was mainly unaffected (Fig. 1e). White blood cell (WBC) count of the mice was not significantly different between WT and Pim1−/− animals, implicating a specifically improved mobilization of LSKs and Sca-1+ cells in Pim1-deficient animals (Fig. 1f).

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Acknowledgements

This work was supported by the Emmy-Noether program of the DFG (DI 1664/1–1), FOR 2033 TP B1, B3 and A4 (NicHem), FOR 2674 A08 DI 1664/3–1, and by the Deutsche Krebshilfe grant DNR 70112614, as well as the Deutsche José Carreras Leukämie-Stiftung (Research grants to SD: DJCLS F15/03, to CK: DJCLS 04F/2016, and to TAM: DJCLS 02 FN/2017).

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  1. These authors contributed equally: Christine Dierks, Justus Duyster

Authors and Affiliations

  1. Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany

    Tony Andreas Müller, Sandra Pennisi, Anabel Zwick, Sarah Decker, Claudius Klein, Benjamin Rister, Alina Rudorf, Sandra Kissel, Marie Follo, Ralph Wäsch, Anna Lena Illert, Dietmar Pfeifer, Christine Dierks & Justus Duyster

  2. Department of Internal Medicine III, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany

    Anabel Zwick & Robert Oostendorp

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

    Anabel Zwick, Alina Rudorf, Anna Lena Illert & Justus Duyster

  4. Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany

    Claudia Waskow

  5. Center for Biological Signaling Studies, EXC294, BIOSS, Freiburg, Germany

    Christine Dierks

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Contributions

TAM, SP, AZ, SD, CK, BR, AR, and SK performed the experiments. MF performed cell sorting. RW and ALI provided mouse strains and materials. TAM analyzed the data. TAM, CD, and JD conceived and designed the experiments and wrote the manuscript.

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Correspondence to Christine Dierks.

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Müller, T.A., Pennisi, S., Zwick, A. et al. PIM1 inhibition effectively enhances plerixafor-induced HSC mobilization by counteracting CXCR4 upregulation and blocking CXCL12 secretion. Leukemia 33, 1296–1301 (2019). https://doi.org/10.1038/s41375-019-0428-6

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