The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence
The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence
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DOI：
10.1038/leu.2008.392
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发表时间：
2009-05-01
期刊：
影响因子：
11.4
通讯作者：
Haas, R.
中科院分区：
文献类型：
--
作者：
Bruns, I.;Czibere, A.;Haas, R.
我们发现CD34+细胞群中细胞亚群的组成在慢性期（CP）慢性髓性白血病（CML）中显着改变。具体来说，普通骨髓祖细胞（CMP）和巨核红细胞祖细胞（MEP）的比例和绝对细胞计数明显高于正常骨髓，而造血干细胞（HSC）的绝对数量是相等的。为了了解其基础，我们对6名CP CML患者和5名健康供者的不同CD34+细胞亚群进行了基因表达谱分析（Affymetrix HU-133A 2.0）。欧几里得距离分析显示CML患者的HSC与正常祖细胞，特别是CMP具有显著的转录相似性。CP CML HSC在转录上比正常HSC与其后代更相似，表明其表型更成熟。因此，CP CML患者与正常供者在HSC上的差异最大，包括CP CML中编码粘附分子的基因、转录因子、干细胞命运调节剂和细胞增殖抑制剂的下调。纤维连接蛋白分离分析和transwell实验分别证实了粘附能力和迁移能力受损。根据我们的研究结果，我们提出CML HSC在脱离小生境时失去静止状态，导致髓系祖细胞的扩增。白血病（2009）23,892 -899；doi: 10.1038 / leu.2008.392;2009年1月22日在线发布
We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors. Leukemia (2009) 23, 892-899; doi:10.1038/leu.2008.392; published online 22 January 2009