Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease
Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease
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DOI：
10.1016/j.ccell.2014.11.002
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发表时间：
2015-01-12
期刊：
影响因子：
50.3
通讯作者：
Clifford, Steven C.
中科院分区：
文献类型：
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作者：
Hill, Rebecca M.;Kuijper, Sanne;Clifford, Steven C.
我们对髓母细胞瘤诊断和复发时的一系列活检进行了全面的临床和生物学研究。MYC家族扩增和P53通路缺陷的组合通常出现在复发时，该组中的所有患者均死于复发后疾病的快速进展。为了研究这种相互作用，我们研究了MYCN驱动的髓母细胞瘤的转基因模型，发现自发发生Trp 53失活突变。该模型中p53功能的消除产生了侵袭性肿瘤，其模拟了具有组合的P53-MYC功能障碍的复发性人类肿瘤的特征。p53活性的恢复以及MYCN的遗传和治疗抑制都降低了肿瘤生长并延长了生存期。我们的研究结果确定了髓母细胞瘤复发时P53-MYC相互作用作为临床侵袭性疾病的生物标志物，可以作为治疗靶点。
We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.