Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.
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DOI：
10.1038/nature22314
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发表时间：
2017-05-25
期刊：
影响因子：
64.8
通讯作者：
Ito T
中科院分区：
文献类型：
--
作者：
Hattori A;Tsunoda M;Konuma T;Kobayashi M;Nagy T;Glushka J;Tayyari F;McSkimming D;Kannan N;Tojo A;Edison AS;Ito T
重新编程的细胞代谢是在各种癌症中观察到的共同特征。然而，代谢变化是否直接调控癌症的发展和进展仍然知之甚少。在这里，我们发现BCAT1，一种支链氨基酸(BCAA)的胞浆氨基转移酶，在慢性粒细胞白血病(CML)中被异常激活，并且在功能上是必需的。BCAT1在CML进展过程中上调，并通过氨化支链酮酸促进白血病细胞中BCAA的产生。阻断BCAT1的表达或酶活性可诱导细胞分化，并抑制BCML(BC-CML)在体内外的增殖。稳定同位素示踪实验与基于核磁共振的代谢分析相结合，证明了BCAT1在细胞内产生支链氨基酸。直接补充BCAA可改善BCAT1基因敲除引起的缺陷，提示BCAT1通过在BC-CML细胞中产生BCAA发挥致癌作用。重要的是，BCAT1的表达不仅在人BC-CML和初治的急性髓系白血病中被激活，而且还预测患者的疾病转归。作为BCAT1表达的上游调节因子，我们发现Musashi2(MSI2)是BC-CML所需的致癌RNA结合蛋白。MSI2在物理上与BCAT1转录本相关，并正向调节其在白血病中的蛋白表达。综上所述，这项工作揭示了通过MSI2-BCAT1轴激活的BCAA代谢改变推动了髓系白血病的癌症进展。
Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for the branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukemia (CML). BCAT1 is up-regulated during CML progression and promotes BCAA production in leukemia cells by aminating the branched-chain keto acids. Blocking BCAT1 expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML (BC-CML) both in vitro and in vivo. Stable isotope tracer experiments combined with NMR-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function via BCAA production in BC-CML cells. Importantly, BCAT1 expression not only is activated in human BC-CML and de novo acute myeloid leukemia but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for BC-CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukemia.
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DOI：
10.1073/pnas.232688199
发表时间：
2003-01-07
影响因子：
11.1
作者：
Qin, XF;An, DS;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
5.3
作者：
Imai, T;Tokunaga, A;Okano, H
通讯作者：
Okano, H
DOI：
10.1038/nrm3522
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
20.3
作者：
Neering, Sarah J.;Bushnell, Timothy;Jordan, Craig T.
通讯作者：
Jordan, Craig T.