Diaz-Blanco E, Bruns I, Neumann F, Fischer J C, Graef T, Rosskopf M, Brors B, Pechtel S, Bork S, Koch A, Baer A, Rohr U-P, Kobbe G, von Haeseler A, Gattermann N, Haas R, Kronenwett R
Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany.
Leukemia. 2007 Mar;21(3):494-504. doi: 10.1038/sj.leu.2404549. Epub 2007 Jan 25.
In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.
在本研究中，我们使用覆盖8746个基因的微阵列，比较了慢性期慢性髓性白血病（CML）未治疗患者骨髓中高度富集的CD34+细胞与正常CD34+细胞的分子特征。表达数据反映了原发性CML祖细胞中几种BCR-ABL诱导的效应，如经典丝裂原活化蛋白激酶途径和磷酸肌醇-3激酶/AKT途径的转录激活以及促凋亡基因IRF8的下调。此外，还鉴定了与正常CD34+细胞相比的新型转录变化。这些变化包括参与转化生长因子β途径的基因、胎儿血红蛋白基因、瘦素受体、索蛋白、金属蛋白酶组织抑制剂1、神经上皮细胞转化基因1的上调以及硒蛋白P的下调。此外，与早期造血干细胞（HSC）和白血病发生相关的基因如HoxA9和MEIS1被转录激活。分化相关基因的差异表达表明CML中CD34+细胞群体的组成发生了改变。慢性期CML CD34+细胞的亚群分析证实了这一点，该分析显示巨核细胞-红系祖细胞的比例增加，而CML中HSC和粒细胞-巨噬细胞祖细胞的比例降低。总之，我们的结果为CML的生物学特性提供了新的见解，并可为鉴定新的治疗靶点提供依据。
