Chen Weili, Kumar Ashish R, Hudson Wendy A, Li Quanzhi, Wu Baolin, Staggs Rodney A, Lund Erik A, Sam Thien N, Kersey John H
University of Minnesota Cancer Center, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455, USA.
Cancer Cell. 2008 May;13(5):432-40. doi: 10.1016/j.ccr.2008.03.005.
The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.
诸如MLL - AF9等致癌基因在人类和小鼠中引发细胞转化及白血病的途径尚未完全明确。在一项针对靶细胞和致癌基因剂量的研究中，我们发现，当处于内源性调控之下时，Mll - AF9能够高效地转化LSK（Lin(-)Sca1(+)c - kit(+)）干细胞，而定向粒细胞 - 单核细胞祖细胞（GMPs）则对转化具有抗性，且不会引发白血病。Mll - AF9在造血干细胞（HSC）中的表达水平高于GMP细胞。在实验中直接显示了Mll - AF9基因剂量效应，即通过逆转录病毒转导产生的高剂量Mll - AF9能够有效地转化GMPs。Mll - AF9上调了LSK和祖细胞中192个基因的表达，但在LSK中的上调水平高于定向髓系祖细胞。
