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首页> 外文期刊>Cell cycle >Histone H2AX suppresses translocations in lymphomas of Eμ-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes
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Histone H2AX suppresses translocations in lymphomas of Eμ-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes

机译：组蛋白H2AX抑制Eμ-c-Myc转基因小鼠淋巴瘤中的易位，该小鼠包含肿瘤促进基因的种系扩增子

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摘要

The DNA damage response (DDR) can restrain the ability of oncogenes to cause genomic instability and drive malignant transformation. The gene encoding the histone H2AX DDR factor maps to 11q23, a region frequently altered in human cancers. Since H2ax functions as a haploinsufficient suppressor of B lineage lymphomas with c-Myc amplification and/or translocation, we determined the impact of H2ax expression on the ability of deregulated c-Myc expression to cause genomic instability and drive transformation of B cells. Neither H2ax deficiency nor haploinsufficiency affected the rate of mortality of Eμ-c-Myc mice from B lineage lymphomas with genomic deletions and amplifications. Yet H2ax functioned in a dosage-dependent manner to prevent unbalanced translocations in Eμ-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among Eμ-c-Myc lymphomas. Regardless of H2ax copy number, all Eμ-c-Myc tumors contained identical amplification of chromosome 19 sequences spanning 20 genes. Many of these genes encode proteins with tumor-promoting activities, including Cd274, which encodes the PD-L1 programmed death ligand that induces T cell apoptosis and enables cancer cells to escape immune surveillance. This amplicon was in non-malignant B and T cells and non-lymphoid cells, linked to the Eμ-c-Myc transgene, and associated with overexpression of PD-L1 on non-malignant B cells. Our data demonstrate that, in addition to deregulated c-Myc expression, non-malignant B lineage lymphocytes of Eμ-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes.
机译：DNA损伤反应（DDR）可以抑制致癌基因引起基因组不稳定和驱动恶性转化的能力。编码组蛋白H2AX DDR因子的基因定位到11q23，这是人类癌症中经常改变的区域。由于H2ax可以作为具有c-Myc扩增和/或易位的B谱系淋巴瘤的单倍​​不足抑制子，因此我们确定了H2ax表达对失调的c-Myc表达引起基因组不稳定和驱动B细胞转化的能力的影响。 H2ax缺乏和单倍体不足均不影响具有基因组缺失和扩增的B谱系淋巴瘤的Eμ-c-Myc小鼠的死亡率。然而，H2ax以剂量依赖的方式起作用，以防止Eμ-c-Myc肿瘤中的不平衡移位，这表明H2ax以单倍不足的方式发挥功能，以抑制等位基因失衡并限制Eμ-c-Myc淋巴瘤内部和之间的分子异质性。无论H2ax拷贝数如何，所有Eμ-c-Myc肿瘤都包含19个20个基因的相同扩增序列。这些基因中的许多编码具有肿瘤促进活性的蛋白质，包括Cd274，其编码PD-L1程序性死亡配体，该配体诱导T细胞凋亡，并使癌细胞能够逃避免疫监视。该扩增子在非恶性B和T细胞和非淋巴样细胞中，与Eμ-c-Myc转基因相连，并与非恶性B细胞上PD-L1的过表达有关。我们的数据表明，除c-Myc表达失调外，Eμ-c-Myc转基因小鼠的非恶性B谱系淋巴细胞可能具有组成型扩增和其他促进肿瘤基因的表达增加。

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