Molecular pathogenesis of disease progression in MLL-rearranged AML.
Molecular pathogenesis of disease progression in MLL-rearranged AML.
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DOI：
10.1038/s41375-018-0253-3
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发表时间：
2019-03
期刊：
影响因子：
11.4
通讯作者：
Makishima H
中科院分区：
文献类型：
--
作者：
Kotani S;Yoda A;Kon A;Kataoka K;Ochi Y;Shiozawa Y;Hirsch C;Takeda J;Ueno H;Yoshizato T;Yoshida K;Nakagawa MM;Nannya Y;Kakiuchi N;Yamauchi T;Aoki K;Shiraishi Y;Miyano S;Maeda T;Maciejewski JP;Takaori-Kondo A;Ogawa S;Makishima H
白血病复发常伴有逐渐侵袭性的临床过程。为了了解白血病复发的分子机制，通过模拟重复复发，将MLL/ af9转化的小鼠白血病细胞连续移植到C57BL/6小鼠（N = 96）身上，通过外显子组测序监测突变（N = 42）。随着移植的进展，白血病的发病逐渐加快，在此期间获得越来越多的体细胞突变（P < 0.005）。其中，Ptpn11 （p.G60R）和Braf （p.V637E）突变与人类MLL-AML中发现的突变相对应，而影响Msn （p.R295C）的复发突变仅在小鼠中观察到，而在人类MLL-AML中没有观察到。另一个令人感兴趣的突变基因是Gnb2，据报道，它在各种血液肿瘤中反复发生突变。Gnb2突变（p.G77R）克隆大小显著增加（P = 0.007），并与白血病发病早期相关（P = 0.011）。与MLL-阴性AML相比，人MLL-AML中GNB2转录本显著上调（P < 0.05），这与MLL/AF9过表达诱导GNB2转录本显著升高（P < 0.001）有关。在体内模型中，GNB2的突变和过表达均可引起白血病的发生，而下调GNB2的表达可降低增殖潜能和生存效益，提示GNB2可能具有驱动作用。总之，随着时间的推移，驱动基因的改变可能在MLL-AML的进展中起重要作用。
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.
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影响因子：
82.9
作者：
通讯作者：
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
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作者：
Seshagiri, Somasekar;Stawiski, Eric W.;Durinck, Steffen;Modrusan, Zora;Storm, Elaine E.;Conboy, Caitlin B.;Chaudhuri, Subhra;Guan, Yinghui;Janakiraman, Vasantharajan;Jaiswal, Bijay S.;Guillory, Joseph;Ha, Connie;Dijkgraaf, Gerrit J. P.;Stinson, Jeremy;Gnad, Florian;Huntley, Melanie A.;Degenhardt, Jeremiah D.;Haverty, Peter M.;Bourgon, Richard;Wang, Weiru;Koeppen, Hartmut;Gentleman, Robert;Starr, Timothy K.;Zhang, Zemin;Largaespada, David A.;Wu, Thomas D.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
16.6
作者：
Okuda H;Kanai A;Ito S;Matsui H;Yokoyama A
通讯作者：
Yokoyama A
影响因子：
50.3
作者：
Yamauchi T;Masuda T;Canver MC;Seiler M;Semba Y;Shboul M;Al-Raqad M;Maeda M;Schoonenberg VAC;Cole MA;Macias-Trevino C;Ishikawa Y;Yao Q;Nakano M;Arai F;Orkin SH;Reversade B;Buonamici S;Pinello L;Akashi K;Bauer DE;Maeda T
通讯作者：
Maeda T