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Molecular Medicine

, Volume 20, Issue 1, pp 736–746 | Cite as

miR-155 Is Associated with the Leukemogenic Potential of the Class IV Granulocyte Colony-Stimulating Factor Receptor in CD34+ Progenitor Cells

  • HaiJiao Zhang
  • Lilia Goudeva
  • Stephan Immenschuh
  • Axel Schambach
  • Julia Skokowa
  • Britta Eiz-Vesper
  • Rainer Blasczyk
  • Constança Figueiredo
Research Article

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a major regulator of granulopoiesis on engagement with the G-CSF receptor (G-CSFR). The truncated, alternatively spliced, class IV G-CSFR (G-CSFRIV) has been associated with defective differentiation and relapse risk in pediatric acute myeloid leukemia (AML) patients. However, the detailed biological properties of G-CSFRIV in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and the potential leukemogenic mechanism of this receptor remain poorly understood. In the present study, we observed that G-CSFRIV-overexpressing (G-CSFRIV+) HSPCs demonstrated an enhanced proliferative and survival capacity on G-CSF stimulation. Cell cycle analyses showed a higher frequency of G-CSFRIV+ cells in the S and G2/M phase. Also, apoptosis rates were significantly lower in G-CSFRIV+ HSPCs. These findings were shown to be associated with a sustained Stat5 activation and elevated miR-155 expression. In addition, G-CSF showed to further induce G-CSFRIV and miR-155 expression of peripheral blood mononuclear cells isolated from AML patients. A Stat5 pharmacological inhibitor or ribonucleic acid (RNA) interference-mediated silencing of the expression of miR-155 abrogated the aberrant proliferative capacity of the G-CSFRIV+ HSPCs. Hence, the dysregulation of Stat5/miR-155 pathway in the G-CSFRIV+ HSPCs supports their leukemogenic potential. Specific miRNA silencing or the inhibition of Stat5-associated pathways might contribute to preventing the risk of leukemogenesis in G-CSFRIV+ HSPCs. This study may promote the development of a personalized effective antileukemia therapy, in particular for the patients exhibiting higher expression levels of G-CSFRIV, and further highlights the necessity of pre-screening the patients for G-CSFR isoforms expression patterns before G-CSF administration.

Notes

Acknowledgments

This work was supported by the Excellence Cluster Rebirth (EXC Unit 6.3). The authors acknowledge Stefanie Vahlsing for her excellent technical assistance. In addition, the authors are grateful to Matthias Ballmaier for help and guidance in the FACS sorting facility.

Supplementary material

10020_2014_2001736_MOESM1_ESM.pdf (1.1 mb)
Supplementary material, approximately 1.06 MB.

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© The Author(s) 2014

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Authors and Affiliations

  • HaiJiao Zhang
    • 1
  • Lilia Goudeva
    • 1
  • Stephan Immenschuh
    • 1
  • Axel Schambach
    • 2
    • 3
  • Julia Skokowa
    • 4
  • Britta Eiz-Vesper
    • 1
  • Rainer Blasczyk
    • 1
    • 3
  • Constança Figueiredo
    • 1
    • 3
  1. 1.Institute for Transfusion MedicineHannover Medical SchoolHannoverGermany
  2. 2.Institute of Experimental HematologyHannover Medical SchoolHannoverGermany
  3. 3.Excellence Cluster “From Regenerative Biology to Reconstructive Therapies,” REBIRTHHannover Medical SchoolHannoverGermany
  4. 4.Department of Oncology, Hematology, Immunology, Rheumatology and PulmonologyUniversity Hospital of TübingenTübingenGermany

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