Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma
Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma
复制标题
DOI：
10.1038/nm.2129
复制
发表时间：
2010-05-01
期刊：
影响因子：
82.9
通讯作者：
Mathas, Stephan
中科院分区：
文献类型：
--
作者：
Lamprecht, Bjoern;Walter, Korden;Mathas, Stephan
哺乳动物基因组包含许多重复元件，包括长末端重复序列（LTR），长期以来一直被怀疑在肿瘤发生中起作用。在这里，我们提出的证据表明，异常LTR激活有助于谱系不适当的基因表达在转化的人类细胞，这种基因表达是肿瘤细胞存活的核心。我们发现，B细胞来源的霍奇金淋巴瘤细胞依赖于非B，骨髓特异性原癌基因集落刺激因子1受体（CSF 1 R）的活性。在这些细胞中，CSF1R转录起始于MaLR家族（THE1B）的异常激活的内源性LTR。MaLR LTR的THE1亚家族的去阻遏在霍奇金淋巴瘤细胞的基因组中广泛存在，并且与由于辅阻遏物CBFA 2T3的表达丧失而导致的表观遗传控制受损相关。此外，我们在间变性大细胞淋巴瘤中检测到LTR驱动的CSF1R转录物，其中CSF1R已知异常表达。我们的结论是，LTR去抑制参与了人类淋巴瘤的发病机制，这一发现可能具有诊断，预后和治疗意义。
Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.