来自加拿大不列颠哥伦比亚省癌症研究中心的科学家揭示了T-ALL中白血病起始细胞活性调控的新机制。揭示了T-ALL中PKC-θ和ROS,表明体内侵袭性生物学行为可能受到促进PKC-θ表达或活性或者ROS积累的治疗策略的限制。

-2012年11月《自然-医学》

中文翻译


【题目】NOTCH1促进T细胞白血病起始活性

【译文】活性氧 (ROS)是细胞代谢的一种副产品,它会损害胞内大分子,当过度出现会促进正常造血干细胞分化和耗竭。 然而,调控这些细胞中ROS的生物学作用和白血病起始细胞(LICs)中ROS数量的机制尚不清楚。本研究表明T细胞急性成淋巴细胞性白血病(T-ALL)(未成熟T细胞前体的恶性肿瘤)中CD44+低ROS亚类在多数侵袭性LICs中高度丰富,ROS积累通过下调蛋白激酶C θ (PKC-θ)而受限制。值得注意的是,缺乏PKC-θ的主要鼠T-ALLs其LIC活性增加,而在缺乏LIC活性的小鼠和人主要T-ALLs中PKC-θ的表达增强。我们的研究还表明PKC-θ被一种新的通路调控,在这个通路中NOTCH1可诱导runt相关转录因子基因3(RUNX3),RUNX3抑制RUNX1,而RUNX1诱导PKC-θ。NOTCH1在T-ALL中通过突变常被激活,并且在小鼠和人模型中对于LIC活性是必需的,因此发挥抑制PKC-θ的作用。这些结果揭示了T-ALL中PKC-θ和ROS,表明体内侵袭性生物学行为可能受到促进PKC-θ表达或活性或者ROS积累的治疗策略的限制。

英文原稿


[Title]: NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species

 [Authors]:Vincenzo Giambra,1 Christopher R Jenkins,1 Hongfang Wang,2 Sonya H Lam,1 Olena O Shevchuk,1 Oksana Nemirovsky,1 Carol Wai,1 Sam Gusscott,1 Mark Y Chiang,3 Jon C Aster,2 R Keith Humphries,1 Connie Eaves1 & Andrew P Weng1

[Abstract]Reactive oxygen species (ROS), a byproduct of cellular metabolism, damage intracellular macromolecules and, when present in excess, can promote normal hematopoietic stem cell differentiation and exhaustion. However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs) and the biological role of ROS in these cells are largely unknown. We show here that the ROSlow subset of CD44+ cells in T cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T cell progenitors, is highly enriched in the most aggressive LICs and that ROS accumulation is restrained by downregulation of protein kinase C θ (PKC-θ). Notably, primary mouse T-ALLs lacking PKC-θ show improved LIC activity, whereas enforced PKC-θ expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-θ is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-θ. NOTCH1, which is frequently activated by mutation in T-ALL and required for LIC activity in both mouse and human models, thus acts to repress PKC-θ. These results reveal key functional roles for PKC-θ and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-θ expression or activity, or the accumulation of ROS.   

原文地址

http://www.nature.com/nm/journal/v18/n11/abs/nm.2960.html

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