MLL2而非MLL1在维持MLL重排的急性髓系白血病中起主要作用。
MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia.
作者信息
Chen Yufei, Anastassiadis Konstantinos, Kranz Andrea, Stewart A Francis, Arndt Kathrin, Waskow Claudia, Yokoyama Akihiko, Jones Kenneth, Neff Tobias, Lee Yoo, Ernst Patricia
机构信息
Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Genomics and Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, BioInnovations Zentrum, Tatzberg 47, Dresden 01307, Germany.
出版信息
Cancer Cell. 2017 Jun 12;31(6):755-770.e6. doi: 10.1016/j.ccell.2017.05.002.
The MLL1 histone 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 for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss 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 in MLL-rearranged leukemia and suggest its broader significance in AML.
MLL1组蛋白甲基转移酶基因会发生许多不同的染色体重排，从而导致预后不良的白血病。剩余的野生型等位基因最常见但并非总是保留下来。野生型等位基因在多大程度上促成白血病发生尚不清楚。在此，我们使用严格、独立的动物模型表明，内源性MLL1对于MLL重排白血病是可有可无的。通过共同缺失最接近的旁系同源基因Mll2来解决潜在的冗余问题。令人惊讶的是，单独缺失Mll2对MLL-AF9转化细胞的存活有显著影响，而额外缺失Mll1会进一步降低细胞活力和增殖。我们表明，MLL1/MLL2的协作并非通过冗余，而是对不同途径的调控。这些发现突出了MLL2作为MLL重排白血病药物靶点的相关性，并表明其在急性髓系白血病中具有更广泛的意义。
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