PDF(Pubmed)
Abstract：
Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial-nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific \"TTGGGGGGTG\" region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2\'s novel function of regulating mitochondrial-nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.
摘要：
急性髓性白血病（AML）由于其频繁复发，儿科和成人患者的生存率均较低。为了阐明AML复发的生物能量原理，我们研究了线粒体-核双基因组的转录调控,这些基因组负责治疗抗性母细胞的代谢可塑性.功能的获得和丧失结果表明，NFκB2是NFκB（活化B细胞的核因子κ-轻链增强子）家族的非经典转录因子（TF），可以控制TFAM（线粒体转录因子A）的表达，已知这对于代谢生物发生至关重要。此外，遗传追踪和启动子分析显示，NFκB2在线粒体中，可以结合调节D-loop域的特定“TTGGGGGGTG”区域，以激活轻链启动子（LSP）和重链启动子1（HSP1），线粒体基因组的启动子。基于我们发现NFκB2调节线粒体-核双重基因组的新功能，我们探索了一种新的三联疗法，包括NFκB2，酪氨酸激酶的抑制剂，和线粒体ATP合酶可有效消除具有FMS相关受体酪氨酸激酶3（FLT3）突变的原发性AML母细胞，并对离体对照细胞表现出最小的毒性。因此，AML的有效治疗必须包括对介导代谢可塑性的双基因组的强抑制作用,以改善白血病预后.
