Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera
Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera
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DOI：
10.1016/s0301-472x(01)00789-5
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发表时间：
2002-03-01
影响因子：
2.6
通讯作者：
Prchal, JT
中科院分区：
文献类型：
--
作者：
Kralovics, R;Guan, YL;Prchal, JT
目标。克隆干细胞增殖和红细胞质量增加是骨髓增殖性疾病真性红细胞增多症 (PV) 的标志。 PV 的分子基础尚不清楚。方法。我们对杂合性丢失 (LOH) 进行了全基因组筛选，并分析了 LOH 位点内的候选基因。结果。在染色体 9p、10q 和 11q 上鉴定出三个基因组区域。这些 LOH 在骨髓细胞和淋巴细胞中的存在表明了它们的干细胞起源。 9pLOH 的患病率约为 33%，是迄今为止 PV 中描述的最常见的染色体病变。我们报告 9pLOH 是由于有丝分裂重组引起的，因此细胞遗传学分析无法检测到 9pLOH。在9pLOH区域内选择了19个候选基因进行测序和表达分析。这些基因没有发现突变；然而，出乎意料的是，在使用9pLOH的PV中的粒细胞和CD34(+)细胞中检测到转录因子NFI-B的表达增加。据报道，NFI 基因家族的一个成员 (NFI-X) 在体外过度表达时会导致 TGF-β 耐药（TGF-β 是已知的造血抑制剂），因此我们将 NFI-B 基因转染至小鼠 32D 细胞系。我们发现 NFI-B 基因的过度表达会在体外赋予 TGF-β 抗性。结论。我们对 9p 号染色体上的一个新区域进行了表征，该区域经常参与 PV 中的 LOH。对该 9pLOH 区域内的基因进行分析揭示了 NFI-B 基因的表达增加。我们的体外研究表明，TGF-J3 抵抗可能是 PV 中克隆干细胞扩增的生理机制。(C) 2002 国际实验血液学会。由爱思唯尔科学公司出版
Objectives. Clonal stem cell proliferation and increased erythrocyte mass are hallmarks of the myeloproliferative disorder polycythemia vera (PV). The molecular basis of PV is unknown.Methods. We carried out a genome-wide screening for loss of heterozygosity (LOH) and analyzed candidate genes within the LOH loci.Results. Three genomic regions were identified on chromosomes 9p, 10q, and 11q. The presence of these LOHs in both myeloid and lymphoid cells indicated their stem cell origin. The 9pLOH prevalence is similar to33% and is the most frequent chromosomal lesion described in PV so far. We report that the 9pLOH is due to mitotic recombination and therefore remains undetectable by cytogenetic analysis. Nineteen candidate genes were selected within the 9pLOH region for sequencing and expression analysis. No mutations were found in these genes; however, unexpectedly, increased expression of the transcription factor NFI-B was detected in granulocytes and CD34(+) cells in PV with 9pLOH. Since a member of the NFI gene family (NFI-X) was reported to result in TGF-beta resistance when overexpressed in vitro (TGF-beta is a known inhibitor of hematopoiesis), we transfected the NFI-B gene to the mouse 32D cell line. We found that overexpression of the NFI-B gene confers TGF-beta resistance in vitro.Conclusions. We characterized a new region on chromosome 9p frequently involved in LOH in PV. Analysis of genes within this 9pLOH region revealed increased expression of the NFI-B gene. Our in vitro studies suggest that TGF-J3 resistance may be the physiologic mechanism of clonal stem cell expansion in PV.(C) 2002 International Society for Experimental Hematology. Published by Elsevier Science Inc.