Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations
Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations
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DOI：
10.1016/j.exphem.2013.12.001
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发表时间：
2014-04-01
影响因子：
2.6
通讯作者：
Dang, Chi V.
中科院分区：
文献类型：
--
作者：
Emadi, Ashkan;Ju, Sung Ah;Dang, Chi V.
新发急性髓系白血病(AML)异柠檬酸脱氢酶1和2(IDH1/2)基因突变的发生率约为20%。这些突变导致不同的代谢特征，包括癌细胞依赖谷氨酰胺作为α-戊二酸的主要来源，α-戊二酸被白血病细胞消耗以产生癌症衍生的代谢物2-羟基戊二酸。我们试图通过测量暴露于小分子谷氨酰胺酶抑制剂BPTES后的细胞生长来在患者突变的IDH原发AML细胞中利用这种谷氨酰胺成瘾的治疗作用。我们发现，与表达野生型IDH的AML细胞相比，BPTES只抑制表达突变型IDH的AML细胞的生长。这项研究为针对特定亚型AML代谢性IDH突变的策略奠定了基础，通过独特的中间代谢重新编程，最终导致癌细胞对谷氨酰胺的依赖以求生存。(C)2014年ISEH--血液学和干细胞学会。由爱思唯尔公司出版。
The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for alpha-ocketoglutarate, which is consumed by leukemia cells to produce a cancer-derived metabolite, 2-hydroxyglutarate. We sought to exploit this glutamine addiction therapeutically in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild type IDH. This study lays the groundwork for strategies to target a specific subtype of AML metabolically with IDH mutations with a unique reprogramming of intermediary metabolism that culminates in glutamine dependency of cancer cells for survival. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.