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

Granulocyte colony stimulating factor (G-CSF) is a major regulator of granulopoiesis upon 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 patients (AML). 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 upon G-CSF stimulation. Cell cycle analyses showed a higher frequency of G-CSFRIV+ cells in 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 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 anti-leukemia 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 prior G-CSF administration.