Division of Cancer Pathobiology; Department of Pathology and Laboratory Medicine; Center for Childhood Cancer Research; Children's Hospital of Philadelphia Research Institute; Philadelphia, PA USA; Abramson Family Cancer Research Institute; Perelman School of Medicine of the University of Pennsylvania; Philadelphia, PA USA.
Cell Cycle. 2013 Sep 1;12(17):2867-75. doi: 10.4161/cc.25922. Epub 2013 Aug 8.
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.
DNA 损伤反应 (DDR) 可以抑制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 因子的基因位于 11q23，这是人类癌症中经常改变的区域。由于 H2ax 作为 c-Myc 扩增和/或易位的 B 谱系淋巴瘤的半不足抑制因子发挥作用，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 缺失或半不足都不影响 B 谱系淋巴瘤基因组缺失和扩增的 Eμ-c-Myc 小鼠的死亡率。然而，H2ax 以剂量依赖的方式发挥作用，可防止 Eμ-c-Myc 肿瘤中的不平衡易位，表明 H2ax 以半不足的方式发挥作用，可抑制等位基因失衡并限制 Eμ-c-Myc 淋巴瘤内和之间的分子异质性。无论 H2ax 拷贝数如何，所有 Eμ-c-Myc 肿瘤均包含跨越 20 个基因的染色体 19 序列的相同扩增。这些基因中的许多编码具有促进肿瘤生长的活性的蛋白质，包括编码 PD-L1 程序性死亡配体的 Cd274，该配体诱导 T 细胞凋亡并使癌细胞逃避免疫监视。这个扩增子存在于非恶性 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 的过表达相关。我们的数据表明，除了失调的 c-Myc 表达外，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性扩增和其他促进肿瘤生长的基因的表达增加。
