Differential proteomic profile of leukemic CD34+ progenitor cells from chronic myeloid leukemia patients
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Maria Rosaria Ricciardi1, Valentina Salvestrini2, Roberto Licchetta1, Simone Mirabilii1, Mattia Forcato3, Gabriele Gugliotta2, Simona Salati3, Fausto Castagnetti2, Gianantonio Rosti2, Massimo Breccia4, Giuliana Alimena4, Rossella Manfredini3, Silvio Bicciato3, Roberto Massimo Lemoli5 and Agostino Tafuri1
1Hematology Unit, Sant'Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
2Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli,” University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
3Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
4Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
5Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
Agostino Tafuri, email: [email protected]
Keywords: chronic myeloid leukemia; CD34+ cells; proteomic profile; cell signaling; apoptosis
Received: July 08, 2017 Accepted: March 06, 2018 Published: April 24, 2018
Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML.
Our results showed that CP-CML CD34+ progenitors were characterized by significant lower phosphorylation of proteins involved in the regulation of growth and cell survival, such as tyrosine kinases of the Src family and members of STAT family, and by a significant higher phosphorylation of p53 (Ser15), compared to normal CD34+ cells from healthy donors. Consistent with these results, cell cycle analysis demonstrated that CP-CML CD34+ cells were characterized by higher percentage of cells in G0-phase compared to normal CD34+ cells. Analysis of expression profile on proteins involved in the apoptotic machinery revealed that, in addition, CD34+ cells from CP-CML were characterized by a significant lower expression of catalase and higher expression of HSP27 and FADD. In sum, we report that CD34+ cells from CP-CML are characterized by a proteomic and phospho-proteomic profile that promotes quiescence through the inhibition of proliferation and the promotion of survival. This differential signaling activation network may be addressed by novel targeted therapies aimed at eradicating CML stem cells.
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