Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Genetics, Genomics & Informatics, The University of Tennessee Health Science Center (UTHSC), Memphis, TN 38103, USA.
Cell Rep. 2020 Jan 14;30(2):454-464.e5. doi: 10.1016/j.celrep.2019.12.048.
Loss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL.
杂合性丢失（LOH）在多种癌症中发生，包括神经母细胞瘤（NBL）。MYCN 扩增和 1p36 缺失与 NBL 中肿瘤侵袭性的标志物紧密相关。尽管远端 1p36 的缺失与单拷贝 MYCN 肿瘤相关，但较大的缺失与 MYCN 扩增相关，表明 1p36 中有两个肿瘤抑制区，其中只有一个促进 MYCN 致癌。为了更好地定义该区域，我们对初级小鼠神经嵴细胞（NCC）中的同源 1p36 基因座进行了基因组编辑，NCC 是 NBL 的起源细胞之一。在体外细胞转化实验中，我们发现 Chd5 缺失赋予了 1p36 LOH 的大部分 MYCN 非依赖性肿瘤抑制作用。相比之下，MYCN 驱动的肿瘤发生从具有随机大小 1p36 缺失的 NCC 池中选择具有 Arid1a 缺失的 NCC，从而确立了 Arid1a 作为与 MYCN 相关的肿瘤抑制因子。我们的研究结果表明，Arid1a 的缺失与致癌性 MYCN 协同作用，并更好地定义了 1p36 LOH 在 NBL 中的肿瘤抑制功能。
