Evidence for Hox and E2A-PBX1 collaboration in mouse T-cell leukemia
Evidence for Hox and E2A-PBX1 collaboration in mouse T-cell leukemia
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DOI：
10.1038/onc.2008.233
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发表时间：
2008-10-01
期刊：
影响因子：
8
通讯作者：
Sauvageau, G.
中科院分区：
文献类型：
--
作者：
Bijl, J.;Krosl, J.;Sauvageau, G.
利用基于小鼠Moloney白血病病毒（MMLV）的前病毒插入突变，我们先前发现e2a - pbx1诱导的淋巴细胞白血病中Hoxa基因位点的一个小区域优先靶向，导致Hoxa基因包括Hoxa10、Hoxa9和Hoxa7过表达。这一观察结果表明Hox基因过表达与e2a - pbx1诱导的淋巴样肿瘤之间存在功能上的相互作用。为了进一步探索这种可能性，我们培育了一系列复合E2A-PBX1 x Hox转基因小鼠，并在体内检测了这些基因在淋巴细胞白血病发生中的遗传相互作用。本报告的结果显示，与对照组E2A-PBX1或Hoxb4幼崽相比，E2A-PBX1 x Hoxb4化合物转基因动物的t细胞白血病发病明显加快。在小鼠中，Hoxa9在加速e2a - pbx1诱导的t细胞白血病方面似乎不如Hoxb4有效。与mmlv诱导的t细胞白血病相比，E2A-PBX1诱导的t细胞白血病表达更高水平的Hoxa基因，这可能表明这些基因对E2A-PBX1转化t细胞有贡献。总的来说，这些数据提供了第一个遗传证据，表明E2A-PBX1和Hox基因在体内淋巴细胞恶性肿瘤中的致癌协同作用，并记录了Hoxa基因亚群在这些白血病中的特异性失调。
Using murine Moloney leukemia virus (MMLV)-based proviral insertional mutagenesis, we previously showed a preferential targeting of a small region in the Hoxa gene locus in E2A-PBX1-induced lymphoid leukemia resulting in the overexpression of several Hoxa genes including Hoxa10, Hoxa9 and Hoxa7. This observation suggested a functional interaction between Hox gene overexpression and E2A-PBX1-induced lymphoid tumors. To further explore this possibility, we generated a series of compound E2A-PBX1 x Hox transgenic mice and tested the genetic interaction between these genes in the generation of lymphoid leukemia in vivo. Results presented in this report show that the onset of T-cell leukemia is significantly ccelerated in E2A-PBX1 x Hoxb4 compound transgenic animals when compared with control E2A-PBX1 or Hoxb4 littermates. Hoxa9 appears less potent than Hoxb4 to accelerate E2A-PBX1-induced T-cell leukemia in mice. E2A-PBX1-induced T-cell leukemias express much higher levels of Hoxa genes than MMLV-induced counterparts, possibly suggesting a contribution of these genes to T-cell transformation by E2A-PBX1. Collectively, these data provide the first genetic evidence showing oncogenic collaboration between E2A-PBX1 and a Hox gene in lymphoid malignancies in vivo and document the specific deregulation of a subgroup of Hoxa genes in these leukemias.