miR-155 Is Associated with the Leukemogenic Potential of the Class IV Granulocyte Colony-Stimulating Factor Receptor in CD34+ Progenitor Cells |
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Authors: | HaiJiao Zhang Lilia Goudeva Stephan Immenschuh Axel Schambach Julia Skokowa Britta Eiz-Vesper Rainer Blasczyk Constan?a Figueiredo |
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Institution: | 1.Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany;2.Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany;3.Excellence Cluster “From Regenerative Biology to Reconstructive Therapies,” REBIRTH, Hannover Medical School, Hannover, Germany;4.Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital of Tübingen, Tübingen, Germany |
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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. |
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