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Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.
Nature Cell Biology ( IF 21.3 ) Pub Date : 2017-Sep-01 , DOI: 10.1038/ncb3597
Sarah J. Horton , George Giotopoulos , Haiyang Yun , Shabana Vohra , Olivia Sheppard , Rachael Bashford-Rogers , Mamunur Rashid , Alexandra Clipson , Wai-In Chan , Daniel Sasca , Loukia Yiangou , Hikari Osaki , Faisal Basheer , Paolo Gallipoli , Natalie Burrows , Ayşegül Erdem , Anastasiya Sybirna , Sarah Foerster , Wanfeng Zhao , Tonci Sustic , Anna Petrunkina Harrison , Elisa Laurenti , Jessica Okosun , Daniel Hodson , Penny Wright , Ken G. Smith , Patrick Maxwell , Jude Fitzgibbon , Ming Q. Du , David J. Adams , Brian J. P. Huntly

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

中文翻译:

Crebbp的早期丧失赋予淋巴样祖细胞恶性干细胞特性。

环状AMP反应元件结合蛋白(CREBBP)的功能丧失突变在淋巴样恶性肿瘤中普遍存在。但是,CREBBP的肿瘤抑制功能尚不清楚。我们证明了在小鼠造血干细胞和祖细胞(HSPCs)中Crebbp的丧失导致B细胞淋巴瘤的发展增加。在此之前,由于对p53的乙酰化作用失败,导致具有过度DNA损伤反应(DDR)缺陷的过度增殖性淋巴祖细胞积聚。我们确定了H3K27ac减少的恶性前淋巴瘤干细胞群体,由于DDR的改变,它经历了转录和遗传进化,导致了淋巴瘤的发生。重要的是,当Crebbp在淋巴细胞生成过程中丢失时,细胞异常丢失并且肿瘤的产生减弱。我们还记录了CREBBP突变可能发生在来自CREBBP突变淋巴瘤患者的HSPC中。这些数据表明,Crebbp的早期丧失有利于淋巴样转化,并有助于淋巴恶性肿瘤的细胞起源和后续进化。
更新日期:2017-09-07
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