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MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia
Cancer Cell ( IF 50.3 ) Pub Date : 2017-06-12 00:00:00 , DOI: 10.1016/j.ccell.2017.05.002
Yufei Chen , Konstantinos Anastassiadis , Andrea Kranz , A. Francis Stewart , Kathrin Arndt , Claudia Waskow , Akihiko Yokoyama , Kenneth Jones , Tobias Neff , Yoo Lee , Patricia Ernst

TheMLL1histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show, using rigorous, independent animal models, that endogenous MLL1 is dispensable forMLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog,Mll2. Surprisingly,Mll2deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additionalMll1loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy, but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target inMLL-rearranged leukemia and suggest its broader significance in AML.

中文翻译:

MLL2,而不是MLL1,在维持MLL重排的急性髓性白血病中起主要作用

该MLL1组蛋白甲基转移酶基因经历许多不同的染色体重排,产生预后差的白血病。剩下的野生型等位基因最常见,但并非总是如此。目前尚不清楚野生型等位基因在多大程度上促成白血病的发生。在这里,我们使用严格的独立动物模型显示,内源性MLL1对于MLL重排的白血病是必不可少的。通过共同删除最接近的对等体Mll2,解决了潜在的冗余问题。出人意料的是,单独的Mll2缺失对MLL-AF9转化的细胞的存活有显着影响,另外的Mll1损失进一步降低了生存力和增殖。我们表明,MLL1 / MLL2协作不是通过冗余,而是通过不同路径的调节。
更新日期:2017-06-13
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