Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation.
Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation.
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DOI：
10.1016/j.ccr.2014.01.032
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发表时间：
2014-03-17
期刊：
影响因子：
50.3
通讯作者：
Langenau DM
中科院分区：
文献类型：
--
作者：
Blackburn JS;Liu S;Wilder JL;Dobrinski KP;Lobbardi R;Moore FE;Martinez SA;Chen EY;Lee C;Langenau DM
克隆进化和肿瘤内异质性通过未知的分子机制驱动癌症进展。为了解决这个问题，使用斑马鱼转基因模型评估了单个t细胞急性淋巴细胞白血病（T-ALL）克隆之间的功能差异。在单个克隆中观察到功能变异，少数克隆随着时间的推移提高了生长速度和白血病繁殖潜力。在这些进化的克隆的一个子集中获得了Akt通路激活，通过激活mTORC1增加了白血病增殖细胞的数量，通过稳定Myc蛋白可能提高了生长速度，并使细胞对地塞米松产生耐药性，通过与Akt抑制剂联合治疗可以逆转这种耐药性。因此，即使在缺乏治疗诱导选择的情况下，T-ALL克隆也会自发地持续进化以驱动白血病的进展。
Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T-cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection.
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影响因子：
56.9
作者：
McCormack, Matthew P.;Young, Lauren F.;Curtis, David J.
通讯作者：
Curtis, David J.
DOI：
10.1073/pnas.0606108103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Palomero, Teresa;Lim, Wei Keat;Ferrando, Adolfo A.
通讯作者：
Ferrando, Adolfo A.
影响因子：
20.3
作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
通讯作者：
Look, A. Thomas
影响因子：
8.8
作者：
Beesley, A. H.;Firth, M. J.;Ford, J.;Weller, R. E.;Freitas, J. R.;Perera, K. U.;Kees, U. R.
通讯作者：
Kees, U. R.
影响因子：
2.7
作者：
Kawamura, M;Ohnishi, H;Hayashi, Y
通讯作者：
Hayashi, Y