Zheng C, Li L, Haak M, Brors B, Frank O, Giehl M, Fabarius A, Schatz M, Weisser A, Lorentz C, Gretz N, Hehlmann R, Hochhaus A, Seifarth W
III. Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Ruprecht-Karls-Universität Heidelberg, Mannheim, Germany.
Leukemia. 2006 Jun;20(6):1028-34. doi: 10.1038/sj.leu.2404227.
Despite recent success in the treatment of early-stage disease, blastic phase (BP) of chronic myeloid leukemia (CML) that is characterized by rapid expansion of therapy-refractory and differentiation-arrested blasts, remains a therapeutic challenge. The development of resistance upon continuous administration of imatinib mesylate is associated with poor prognosis pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. To identify transcriptional signatures that may explain pathological characteristics and aggressive behavior of BP blasts, we performed comparative gene expression profiling on CD34+ Ph+ cells purified from patients with untreated newly diagnosed chronic phase CML (CP, n=11) and from patients in BP (n=9) using Affymetrix oligonucleotide arrays. Supervised microarray data analysis revealed 114 differentially expressed genes (P<10(-4)), 34 genes displaying more than two-fold transcriptional changes when comparing CP and BP groups. While 24 of these genes were downregulated, 10 genes, especially suppressor of cytokine signalling 2 (SOCS2), CAMPATH-1 antigen (CD52), and four human leukocyte antigen-related genes were strongly overexpressed in BP. Expression of selected genes was validated by real-time-polymerase chain reaction and flow cytometry. Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy.
尽管近期在早期疾病治疗方面取得了成功，但慢性髓性白血病（CML）的急变期（BP）仍面临治疗挑战，该阶段以治疗难治且分化停滞的原始细胞快速增殖为特征。持续给予甲磺酸伊马替尼后出现的耐药性与预后不良相关，这表明需要替代治疗策略，并更好地理解疾病进展的分子机制。为了确定可能解释BP原始细胞病理特征和侵袭行为的转录特征，我们使用Affymetrix寡核苷酸阵列对从未经治疗的新诊断慢性期CML（CP，n = 11）患者和BP期患者（n = 9）中纯化的CD34 + Ph +细胞进行了比较基因表达谱分析。监督微阵列数据分析揭示了114个差异表达基因（P < 10（-4）），在比较CP组和BP组时，有34个基因显示出超过两倍的转录变化。其中24个基因下调，而10个基因，特别是细胞因子信号转导抑制因子2（SOCS2）、CAMPATH-1抗原（CD52）和四个人类白细胞抗原相关基因在BP中强烈过表达。通过实时聚合酶链反应和流式细胞术验证了所选基因的表达。我们的数据表明CML-BP存在共同的基因表达谱，并为与疾病进展和高恶性相关的原始细胞分子表型提供了新的见解。
