Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation.
Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation.
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DOI：
10.1111/cas.15098
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发表时间：
2021-10
期刊：
影响因子：
5.7
通讯作者：
Kurokawa M
中科院分区：
文献类型：
--
作者：
Mizuno H;Koya J;Masamoto Y;Kagoya Y;Kurokawa M
Evi1是急性髓性白血病（AML）发生和进展所必需的转录因子，高Evi1水平的AML与极差的临床预后相关。由于靶向代谢易损性是癌症的新兴治疗策略，我们在此通过分析小鼠高Evi1白血病细胞的转录组学、表观遗传学和代谢组学分析，研究了一个新的Evi1治疗靶点。我们发现，Evi1过表达和Evi1驱动的白血病转化上调糖异生酶Fbp1和其他戊糖磷酸酶的转录，Evi1与这些基因的增强子区相互作用。利用过表达Evi1的白血病细胞进行代谢组学分析，发现过表达Evi1可上调戊糖磷酸途径。通过shRNA介导的敲低抑制Fbp1和戊糖磷酸途径酶选择性地减少体外Evi1驱动的白血病发生。此外，在继发性移植过表达Evi1的白血病小鼠中，药理或shRNA介导的Fbp1抑制显著降低了白血病细胞负荷。总之，靶向FBP1是一种很有前途的治疗高Evi1 AML的策略。活化的戊糖磷酸途径促进过表达Evi1的白血病的进展。Fbp1和其他葡萄糖代谢相关基因共同上调戊糖磷酸途径的活性。
Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1‐driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1‐overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA‐mediated knockdown selectively decreased Evi1‐driven leukemogenesis in vitro. Moreover, pharmacological or shRNA‐mediated Fbp1 inhibition in secondarily transplanted Evi1‐overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML. The activated pentose phosphate pathway enhances progression of Evi1‐overexpressing leukemia. Fbp1 and other glucose metabolism‐related genes cooperatively upregulate pentose phosphate pathway activity.
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影响因子：
82.9
作者：
Guo B;Huang X;Lee MR;Lee SA;Broxmeyer HE
通讯作者：
Broxmeyer HE
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1084/jem.20110447
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kataoka K;Sato T;Yoshimi A;Goyama S;Tsuruta T;Kobayashi H;Shimabe M;Arai S;Nakagawa M;Imai Y;Kumano K;Kumagai K;Kubota N;Kadowaki T;Kurokawa M
通讯作者：
Kurokawa M
影响因子：
8.8
作者：
Gelman SJ;Naser F;Mahieu NG;McKenzie LD;Dunn GP;Chheda MG;Patti GJ
通讯作者：
Patti GJ
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ