7Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors
7Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors
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DOI：
10.1038/nm.3993
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发表时间：
2015-12-01
期刊：
影响因子：
82.9
通讯作者：
So, Chi Wai Eric
中科院分区：
文献类型：
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作者：
Esposito, Maria Teresa;Zhao, Lu;So, Chi Wai Eric
急性髓性白血病（AML）主要由致癌转录因子驱动，这些转录因子通常被视为使用小分子抑制剂方法的难治性靶点。在这里，我们证明了由抑制性转录因子驱动的AML，包括AML 1-ETO（由融合癌基因RUNX 1-RUNX 1 T1编码）和PML-RAR α融合癌蛋白（由PML-RARA编码）对聚（ADP-核糖）聚合酶（PARP）抑制极其敏感，部分原因是它们抑制了关键同源重组（HR）相关基因的表达及其受损的DNA损伤反应（DDR）。相反，由具有显性反式激活能力的混合谱系白血病（MLL，由KMT 2A编码）融合体驱动的白血病精通DDR并且对PARP抑制不敏感。有趣的是，MLL下游靶点HOXA 9的遗传或药理学抑制（其激活各种HR相关基因的表达）损害DDR并使MLL白血病对PARP抑制剂（PARPis）敏感。相反，HOXA 9过表达赋予PARPi对AML 1-ETO和PML-RAR α转化细胞的抗性。总之，这些研究描述了PARPi诱导的合成致死性用于白血病治疗的潜在效用，并揭示了控制AML中PARPi敏感性的新分子机制。
Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RAR alpha fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RAR alpha transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.