Gerber Jonathan M, Gucwa Jessica L, Esopi David, Gurel Meltem, Haffner Michael C, Vala Milada, Nelson William G, Jones Richard J, Yegnasubramanian Srinivasan
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
Oncotarget. 2013 May;4(5):715-28. doi: 10.18632/oncotarget.990.
The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (MYCN, TIMELESS); downregulation of pro-differentiation and TGF-β/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g., CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication these cells and achieve cure.
尽管酪氨酸激酶抑制（TKI）治疗，但慢性髓性白血病（CML）中白血病干细胞（LSCs）的持续存在可能解释了TKI停药后的复发。在此，我们使用外显子微阵列对高度纯化的CML以及正常干细胞和祖细胞群体进行了全基因组转录组分析，以确定根除CML LSCs的新靶点。我们鉴定出97个在CML与正常干细胞和祖细胞中差异表达的基因。这些基因包括在CML LSCs中显著上调的细胞表面基因：二肽基肽酶4（DPP4，即CD26）、白细胞介素2受体A（IL2RA，即CD25）、蛋白酪氨酸磷酸酶受体D（PTPRD）、钙通道Cav1.3（CACNA1D）、白细胞介素1受体辅助蛋白（IL1RAP）、溶质载体家族4成员4（SLC4A4）和钾通道亚家族K成员5（KCNK5）。对LSCs的进一步分析揭示了正常细胞过程的失调，关键癌症信号通路中的基因可变剪接证明了这一点，如p53信号通路（如PERP、细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A））、激酶结合（如双特异性磷酸酶12（DUSP12）、肌动蛋白结合蛋白（MARCKS））和细胞增殖（MYCN、无时间蛋白（TIMELESS））；促分化和转化生长因子-β/骨形态发生蛋白（TGF-β/BMP）信号通路下调；氧化代谢和DNA修复通路上调；以及包括趋化因子CCL2在内的炎性细胞因子和多个癌基因（如细胞周期蛋白D1（CCND1））的激活。这些数据是理解CML LSCs分子变化的重要资源，可用于开发根除这些细胞并实现治愈的新疗法。
