miR-155 is associated with the leukemogenic potential of the class IV granulocyte colony-stimulating factor receptor in CD34⁺ progenitor cells.
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.
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
HaiJiao
H
Zhang
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
Lilia
L
Goudeva
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
Stephan
S
Immenschuh
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.|Excellence Cluster "From Regenerative Biology to Reconstructive Therapies," REBIRTH, Hannover Medical School, Hannover, Germany.
Axel
A
Schambach
Department of Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital of Tübingen, Tübingen, Germany.
Julia
J
Skokowa
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
Britta
B
Eiz-Vesper
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.|Excellence Cluster "From Regenerative Biology to Reconstructive Therapies," REBIRTH, Hannover Medical School, Hannover, Germany.
Rainer
R
Blasczyk
Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.|Excellence Cluster "From Regenerative Biology to Reconstructive Therapies," REBIRTH, Hannover Medical School, Hannover, Germany.
Constança
C
Figueiredo
D018952:Antigens, CD34; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism
D018952:Antigens, CD34; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor