Prall Wolf C, Czibere Akos, Grall Franck, Spentzos Dimitrios, Steidl Ulrich, Giagounidis Aristoteles Achilles Nikolaus, Kuendgen Andrea, Otu Hasan, Rong Astrid, Libermann Towia A, Germing Ulrich, Gattermann Norbert, Haas Rainer, Aivado Manuel
Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University, Nussbaumstraße 20, 80336, Munich, Germany.
Int J Hematol. 2009 Mar;89(2):173-187. doi: 10.1007/s12185-008-0242-9. Epub 2009 Jan 20.
One feature of the molecular pathology of myelodysplastic syndromes (MDS) is aberrant gene expression. Such aberrations may be related to patient survival, and may indicate to novel diagnostic and therapeutic targets. Therefore, we aimed at identifying aberrant gene expression that is associated with MDS and patient survival. Bone marrow-derived CD34+ hematopoietic progenitor cells from six healthy persons and 16 patients with MDS were analyzed on cDNA macroarrays comprising 1,185 genes. Thereafter, our patients were followed-up for 54 months. We found differential expression of genes that were hitherto unrecognized in the context of MDS. Differential expression of 10 genes was confirmed by quantitative real-time RT-PCR. Hierarchical cluster analysis facilitated the separation of CD34+ cells of normal donors from patients with MDS. More importantly, it also distinguished MDS-patients with short and long survival. Scrutinizing our cDNA macroarray data for genes that are associated with short survival, we found, among others, increased expression of six different genes that encode the proteasome subunits. On the other hand, the most differentially down-regulated gene was IEX-1, which encodes an anti-apoptotic protein. We confirmed its decreased expression on RNA and protein level in an independent validation set of patient samples. The presented data broadens our notion about the molecular pathology of MDS and may lend itself to better identify patients with short survival. Furthermore, our findings may help to define new molecular targets for drug development and therapeutic approaches for patients with poor prognosis.
骨髓增生异常综合征（MDS）分子病理学的一个特征是基因表达异常。此类异常可能与患者的生存率相关，并且可能提示新的诊断和治疗靶点。因此，我们旨在识别与MDS及患者生存率相关的异常基因表达。我们在包含1185个基因的cDNA宏阵列上分析了来自6名健康人和16名MDS患者的骨髓源性CD34+造血祖细胞。此后，对我们的患者进行了54个月的随访。我们发现了一些在MDS背景下此前未被认识到的基因差异表达。通过定量实时RT-PCR证实了10个基因的差异表达。层次聚类分析有助于将正常供体的CD34+细胞与MDS患者的细胞区分开来。更重要的是，它还区分了生存期短和长的MDS患者。在我们的cDNA宏阵列数据中仔细查找与短生存期相关的基因时，我们发现，除其他外，编码蛋白酶体亚基的6种不同基因的表达增加。另一方面，差异下调最明显的基因是IEX-1，它编码一种抗凋亡蛋白。我们在一个独立的患者样本验证集中证实了其在RNA和蛋白质水平上的表达降低。所呈现的数据拓宽了我们对MDS分子病理学的认识，并可能有助于更好地识别生存期短的患者。此外，我们的发现可能有助于为药物开发定义新的分子靶点，并为预后不良的患者确定治疗方法。
