Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.
Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.
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SIRT6酶活性的耗竭增加了急性髓细胞性白血病细胞对DNA损害剂的脆弱性。
DOI：
10.3324/haematol.2017.176248
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发表时间：
2018-01
期刊：
影响因子：
10.1
通讯作者：
Cea M
中科院分区：
文献类型：
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作者：
Cagnetta A;Soncini D;Orecchioni S;Talarico G;Minetto P;Guolo F;Retali V;Colombo N;Carminati E;Clavio M;Miglino M;Bergamaschi M;Nahimana A;Duchosal M;Todoerti K;Neri A;Passalacqua M;Bruzzone S;Nencioni A;Bertolini F;Gobbi M;Lemoli RM;Cea M
基因组不稳定性在包括急性髓性白血病（AML）在内的各种恶性肿瘤中起着病理作用，因此代表了潜在的治疗靶点。最近的研究表明，SIRT 6是一种NAD+依赖的核脱乙酰酶，通过在不同的肿瘤细胞中保持DNA完整性而发挥基因组监护人的作用。在这里，我们证明了来自AML患者的CD 34+原始细胞也显示出持续的DNA损伤和SIRT 6过表达。事实上，我们确定了一个预后不良的患者子集，具有广泛的不稳定性，依赖SIRT 6来补偿DNA复制应激。因此，SIRT 6的缺失损害了白血病细胞修复DNA双链断裂的能力，这反过来又增加了它们对柔红霉素和Ara-C的敏感性，无论是在体外还是体内。相反，在正常的CD 34+造血祖细胞中观察到的低SIRT 6水平解释了它们对遗传毒性应激的较弱敏感性。有趣的是，我们已经确定DNA-PKcs和CtIP脱乙酰化对于SIRT 6介导的DNA修复至关重要。总之，我们的数据表明，白血病细胞中SIRT 6的失活导致DNA修复机制的破坏，基因组不稳定性和侵袭性AML。这种合成致死方法，增强DNA损伤，同时伴随阻断修复反应，提供了SIRT 6调节剂治疗白血病的临床评价的基本原理。
Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo. In contrast, low SIRT6 levels observed in normal CD34+ hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.