The transcription factor Evi1 has an outstanding role in the formation and transformation of hematopoietic cells. Its activation by chromosomal rearrangement induces a myelodysplastic syndrome with progression to acute myeloid leukemia of poor prognosis. Similarly, retroviral insertion-mediated upregulation confers a competitive advantage to transplanted hematopoietic cells, triggering clonal dominance or even leukemia. To study the molecular and functional response of primary murine hematopoietic progenitor cells to the activation of Evi1, we established an inducible lentiviral expression system. EVI1 had a biphasic effect with initial growth inhibition and retarded myeloid differentiation linked to enhanced survival of myeloblasts in long-term cultures. Gene expression microarray analysis revealed that within 24 h EVI1 upregulated 'stemness' genes characteristic for long-term hematopoietic stem cells (Aldh1a1, Abca1, Cdkn1b, Cdkn1c, Epcam, among others) but downregulated genes involved in DNA replication (Cyclins and their kinases, among others) and DNA repair (including Brca1, Brca2, Rad51). Cell cycle analysis demonstrated EVI1's anti-proliferative effect to be strictly dose-dependent with accumulation of cells in G0/G1, but preservation of a small fraction of long-term proliferating cells. Although confined to cultured cells, our study contributes to new hypotheses addressing the mechanisms and molecular targets involved in preleukemic clonal dominance or leukemic transformation by Evi1.

译文

:转录因子Evi1在造血细胞的形成和转化中具有杰出的作用。其通过染色体重排的激活诱导骨髓增生异常综合症,并发展为预后较差的急性髓细胞性白血病。同样,逆转录病毒插入介导的上调赋予移植的造血细胞竞争优势,引发克隆优势甚至白血病。为了研究原代小鼠造血祖细胞对Evi1激活的分子和功能反应,我们建立了可诱导的慢病毒表达系统。 EVI1具有双相作用,具有初始生长抑制作用,并且延缓了骨髓分化,与长期培养中成纤维细胞的存活率提高有关。基因表达芯片分析表明,EVI1在24h内上调了长期造血干细胞(Aldh1a1,Abca1,Cdkn1b,Cdkn1c,Epcam等)特有的“茎”基因,但下调了与DNA复制有关的基因(Cyclins及其激酶,以及DNA修复(包括Brca1,Brca2,Rad51)。细胞周期分析表明,EVI1的抗增殖作用与G0 / G1中的细胞积累严格地呈剂量依赖性,但保留了一小部分长期增殖的细胞。尽管仅限于培养的细胞,但我们的研究为解决Evi1在白血病前克隆优势或白血病转化中涉及的机制和分子靶点的新假设做出了贡献。

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