Ricciardi Maria Rosaria, Salvestrini Valentina, Licchetta Roberto, Mirabilii Simone, Forcato Mattia, Gugliotta Gabriele, Salati Simona, Castagnetti Fausto, Rosti Gianantonio, Breccia Massimo, Alimena Giuliana, Manfredini Rossella, Bicciato Silvio, Lemoli Roberto Massimo, Tafuri Agostino
Hematology Unit, Sant'Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli," University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.
Oncotarget. 2018 Apr 24;9(31):21758-21769. doi: 10.18632/oncotarget.24938.
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.
慢性髓性白血病（CML）是一种由罕见的静止细胞群体维持的干细胞疾病，这些静止细胞在一定程度上对酪氨酸激酶抑制剂（TKIs）具有抗性。BCR-ABL癌基因激活多种相互作用的信号转导通路（STP），如RAS/MEK/ERK、PI3K/Akt、Wnt和STAT5，导致克隆细胞异常增殖。从这个角度来看，本研究的目的是分析参与慢性期（CP）CML祖细胞CD34+细胞增殖/静止和存活机制的STP的表达和激活谱。我们的结果表明，与健康供体的正常CD34+细胞相比，CP-CML CD34+祖细胞的特征在于参与生长和细胞存活调节的蛋白质（如Src家族的酪氨酸激酶和STAT家族成员）的磷酸化水平显著降低，以及p53（Ser15）的磷酸化水平显著升高。与这些结果一致，细胞周期分析表明，与正常CD34+细胞相比，CP-CML CD34+细胞的特征在于G0期细胞百分比更高。对凋亡机制相关蛋白质表达谱的分析表明，此外，CP-CML的CD34+细胞的特征还在于过氧化氢酶的表达显著降低，以及HSP27和FADD的表达升高。总之，我们报告CP-CML的CD34+细胞具有蛋白质组学和磷酸化蛋白质组学特征，通过抑制增殖和促进存活来促进静止。这种差异信号激活网络可能通过旨在根除CML干细胞的新型靶向疗法来解决。
