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Lenalidomide-induced upregulation of CXCR4 in CD34+ hematopoietic cells, a potential mechanism of decreased hematopoietic progenitor mobilization

Leukemia volume 27, pages 1407–1411 (2013)Cite this article

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Immunomodulatory derivatives of thalidomide (IMiD compounds) like lenalidomide (LEN) have impressive clinical activity in patients with both relapsed or refractory and newly diagnosed multiple myeloma.1 Hematopoietic stem cell (HSC) transplantation is still the ‘backbone’ in the treatment of newly diagnosed multiple myeloma patients and very often combined with LEN in order to achieve high response rates.2 Unfortunately, clinical data have shown that in up to 43% of patients, standard mobilization with granulocyte colony-stimulating factor (G-CSF) alone failed to mobilize hematopoietic progenitors, raising concerns about potential stem cell toxicity of LEN.3, 4 We have shown that neither LEN nor pomalidomide (POM) are toxic to HSC,5, 6 and it is known that mobilization of CD34+ cells with Plerixafor (AMD3100) overcomes mobilization failures after LEN treatment.7 The fact that AMD3100 antagonizes the binding of the chemokine stromal-cell-derived factor-1α (SDF-1α) to its receptor CXC chemokine receptor 4 (CXCR4) suggests a potential role of the CXCR4/SDF-1α axis in mediating mobilization failure after LEN treatment. To further analyze why blocking CXCR4 by AMD3100 overcomes mobilization failure to G-CSF in LEN-treated patients, we analyzed the effects of LEN on CXCR4 expression and function in CD34+ cells.

It is known that the cell surface expression of CXCR4 can be low, whereas a large part of CXCR4 protein is sequestered intracellularly in CD34+ cells.9 To investigate whether the increased CXCR4 surface expression after LEN exposure was due to an increase of total CXCR4 expression or CXCR4 translocation from the cytoplasm to the cell membrane, we performed real-time PCR and western blot assays to determine the total CXCR4 mRNA and protein level. We found that neither LEN nor POM increased the total CXCR4 mRNA or CXCR4 protein level (Figures 1b and c). But separate analysis of the hydrophobic (membrane) and the hydrophilic (cytosol) cell fraction by western blot revealed that the CXCR4 protein significantly increased in the membrane portion after LEN treatment, suggesting the translocation of CXCR4 to the CD34+ cell surface (Figure 1d). The translocation of CXCR4 to the cell membrane induced by LEN was further confirmed by immunofluorescence microscopy. In CD34+ cells without treatment, CXCR4 showed an even localization in the whole cell. In contrast, LEN treatment induced the cell surface accumulation of CXCR4 in CD34+ cells as seen in Figure 1e.

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Acknowledgements

We thank Dr Peter L Hordijk from Sanquin Research at CLB for provide the LZRS-CXCR4-GFP-IRES-Zeocin vector. This research was supported in part by grants from the Leukemia and Lymphoma Society and Multiple Myeloma Research foundation. Dr Mapara is supported by the NIH RO1HL093716.

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  1. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    S Li, J Fu, H Ma, M Y Mapara & S Lentzsch

  2. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S Li, J Fu, H Ma, M Y Mapara & S Lentzsch

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S Lentzsch receives research funding from Celgene Corporation. The remaining authors declare no conflict of interest.

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Li, S., Fu, J., Ma, H. et al. Lenalidomide-induced upregulation of CXCR4 in CD34+ hematopoietic cells, a potential mechanism of decreased hematopoietic progenitor mobilization. Leukemia 27, 1407–1411 (2013). https://doi.org/10.1038/leu.2012.323

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