PDF(Pubmed)
Abstract：
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-ETO is one of the most common subtypes of AML. Although t(8;21) AML has been classified as favorable-risk, only about half of patients are cured with current therapies. Several genetic abnormalities, including TP53 mutations and deletions, negatively impact survival in t(8;21) AML. In this study, we established Cas9+ mouse models of t(8;21) AML with intact or deficient Tpr53 (a mouse homolog of TP53) using a retrovirus-mediated gene transfer and transplantation system. Trp53 deficiency accelerates the in vivo development of AML driven by RUNX1-ETO9a, a short isoform of RUNX1-ETO with strong leukemogenic potential. Trp53 deficiency also confers resistance to genetic depletion of RUNX1 and a TP53-activating drug in t(8;21) AML. However, Trp53-deficient t(8;21) AML cells were still sensitive to several drugs such as dexamethasone. Cas9+ RUNX1-ETO9a cells with/without Trp53 deficiency can produce AML in vivo, can be cultured in vitro for several weeks, and allow efficient gene depletion using the CRISPR/Cas9 system, providing useful tools to advance our understanding of t(8;21) AML.
摘要：
急性髓系白血病(AML)伴t(8;21)(q22;q22.1);RUNX1-ETO是AML最常见的亚型之一。虽然t(8；21)AML已被归类为有利风险，只有大约一半的患者用目前的疗法治愈。几种遗传异常，包括TP53突变和缺失，对t（8；21）AML的生存率产生负面影响。在这项研究中,我们使用逆转录病毒介导的基因转移和移植系统建立了t(8;21)AML的Cas9+小鼠模型,该模型具有完整或缺陷的Tpr53(TP53的小鼠同源物).Trp53缺乏加速由RUNX1-ETO9a驱动的AML的体内发展，RUNX1-ETO的短同工型，具有强的致瘤潜能。Trp53缺陷还赋予对t(8;21)AML中RUNX1和TP53激活药物的遗传耗竭的抗性。然而,Trp53缺陷的t(8;21)AML细胞仍然对几种药物如地塞米松敏感。有/没有Trp53缺陷的Cas9+RUNX1-ETO9a细胞可以在体内产生AML，可以在体外培养几周，并允许使用CRISPR/Cas9系统进行有效的基因消耗，提供有用的工具来增进我们对t(8；21)AML的理解。
