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Nature:一种DNA修复酶对肿瘤的促进作用

摘要 : 美国国立卫生研究院国家癌症研究所等处的研究人员揭示,基因组卫士在AML中执行由致癌基因诱导的分化阻断功能方面所起的一个出乎意料的肿瘤促进作用,同时也提出这样一个可能性:DNA修复通道抑制剂可能具有针对白血病的活性。相关文章发表于2014年7月27日的《Nature》杂志上。
缺乏MLL4的骨髓造血

缺乏MLL4的骨髓造血

自我更新(造血干细胞的决定性特征)受到活性氧簇的积累和DNA双链断裂的限制。André Nussenzweig及同事在这篇论文中对DNA损伤是否也会限制白血病干细胞自我更新和恶性造血进行了研究。

他们发现,组蛋白甲基转移酶MLL4 (DNA修复中所涉及的一种酶)是干细胞活性和携带MLL-AF9致癌基因的一种侵袭性“急性髓性白血病”(AML) 所需的。MLL4的删除会增强骨髓细胞生成和白血病母细胞的骨髓分化,这会防止小鼠发生与AML相关的死亡。

这些发现揭示了基因组卫士在AML中执行由致癌基因诱导的分化阻断功能方面所起的一个出乎意料的肿瘤促进作用,同时也提出这样一个可能性:DNA修复通道抑制剂可能具有针对白血病的活性。

原文摘要:

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

Margarida A. Santos, Robert B. Faryabi, Aysegul V. Ergen, Amanda M. Day, Amy Malhowski,Andres Canela, Masahiro Onozawa, Ji-Eun Lee, Elsa Callen, Paula Gutierrez-Martinez,Hua-Tang Chen, Nancy Wong, Nadia Finkel, Aniruddha Deshpande, Susan Sharrow,Derrick J. Rossi, Keisuke Ito, Kai Ge, Peter D. Aplan, Scott A. Armstrong & André Nussenzweig

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL–AF9 oncogene. Deletion ofMLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4−/− MLL–AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL–AF9 blasts, which requires cyclin-dependent kinase inhibitor p21Cip1(Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

来源: Nature中文 浏览次数:214

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