MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation.
MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation.
复制标题
MEIS 2是一种肾上腺素能核心调节转录因子，参与TH-MYCN驱动的神经母细胞瘤形成的早期启动。
DOI：
10.3390/cancers13194783
复制
发表时间：
2021-09-24
期刊：
影响因子：
5.2
通讯作者：
Durinck K
中科院分区：
文献类型：
--
作者：
De Wyn J;Zimmerman MW;Weichert-Leahey N;Nunes C;Cheung BB;Abraham BJ;Beckers A;Volders PJ;Decaesteker B;Carter DR;Look AT;De Preter K;Van Loocke W;Marshall GM;Durbin AD;Speleman F;Durinck K
神经母细胞瘤是起源于交感神经系统的儿科肿瘤，占所有儿童癌症死亡的10-15%。所有神经母细胞瘤患者中有一半患有高风险疾病，其中近50%复发并死于疾病。此外，标准疗法会导致严重的终身副作用，并增加继发性肿瘤的风险。进一步的研究对于更好地理解神经母细胞瘤的分子基础和识别新的可药用靶点至关重要。神经母细胞瘤肿瘤发生已经为此在小鼠和斑马鱼中建模。在这里，我们提出了一个详细的解剖的基因表达模式，肿瘤形成的小鼠TH-MYCN驱动的神经母细胞瘤模型。我们确定了对神经母细胞瘤肿瘤起始与肿瘤进展非常重要的关键因素，确定了神经母细胞瘤发展过程中观察到的表达模式的关键调节因子，并仔细检查了哪些因素可能是治疗干预的创新和脆弱节点。大约一半的高危神经母细胞瘤患者存在MYCN扩增。MYCN过表达在这种侵袭性儿科肿瘤中的分子后果已经研究了几十年，但到目前为止，我们对MYCN驱动的肿瘤形成的早期起始步骤的理解仍然是谜。我们在小鼠TH-MYCN驱动的神经母细胞瘤肿瘤形成过程中的不同时间点进行了详细的转录组美化。神经母细胞瘤依赖因子MEIS 2与ASCL 1一起被确定为候选肿瘤起始因子，并被证明是肾上腺素能神经母细胞瘤中新的核心调节回路成员。进一步感兴趣的是，我们发现了一个KEOPS复合体成员（gm 6890），涉及同源双链断裂修复和端粒维持，在肿瘤形成过程中强烈上调，以及检查点衔接子Claspin（CLSPN）和三个染色体17 q位点CBX 2，GJC 1和LIMD 2。最后，跨物种主调节因子分析确定了FOXM 1，以及控制MYCN驱动的神经母细胞瘤转录组谱的其他枢纽。总之，早期增生性病变和成熟MYCN驱动的神经母细胞瘤的时间分辨转录组分析产生了与肿瘤起始和维持有关的新组分，为MYCN驱动的神经母细胞瘤提供了推定的新药物靶点。
Neuroblastoma is a pediatric tumor originating from the sympathetic nervous system responsible for 10–15% of all childhood cancer deaths. Half of all neuroblastoma patients present with high-risk disease, of which nearly 50% relapse and die of their disease. In addition, standard therapies cause serious lifelong side effects and increased risk for secondary tumors. Further research is crucial to better understand the molecular basis of neuroblastomas and to identify novel druggable targets. Neuroblastoma tumorigenesis has to this end been modeled in both mice and zebrafish. Here, we present a detailed dissection of the gene expression patterns that underlie tumor formation in the murine TH-MYCN-driven neuroblastoma model. We identified key factors that are putatively important for neuroblastoma tumor initiation versus tumor progression, pinpointed crucial regulators of the observed expression patterns during neuroblastoma development and scrutinized which factors could be innovative and vulnerable nodes for therapeutic intervention. Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.
登录
查看更多内容
影响因子：
6
作者：
Alam, Goleeta;Cui, Hongjuan;Ding, Han-Fei
通讯作者：
Ding, Han-Fei
DOI：
10.1038/s41580-020-0215-2
发表时间：
2020-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baluapuri A;Wolf E;Eilers M
通讯作者：
Eilers M
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM
影响因子：
16.6
作者：
Bianco, Julien N.;Bergoglio, Valerie;Pasero, Philippe
通讯作者：
Pasero, Philippe
影响因子：
158.5
作者：
Bown, N;Cotterill, S;Speleman, F
通讯作者：
Speleman, F