Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition
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DOI：
10.1182/blood-2015-01-621870
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发表时间：
2015-09-10
期刊：
影响因子：
20.3
通讯作者：
Bouscary, Didier
中科院分区：
文献类型：
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作者：
Jacque, Nathalie;Ronchetti, Anne Marie;Bouscary, Didier
癌细胞需要谷氨酰胺来适应增加的生物合成活性。细胞内谷氨酰胺分解代谢的限制步骤涉及谷氨酰胺酶（GA）将其转化为谷氨酸。人类不同的GA亚型由GLS1和GLS2基因编码。在此，我们表明谷氨酰胺水平控制线粒体氧化磷酸化（OXPHOS）在急性髓性白血病（AML）细胞。谷氨酰胺酶C （GAC）是AML中表达最丰富的ga异构体。药物CB-839敲低GLS1表达和药理学抑制GLS1均可降低OXPHOS，导致白血病细胞增殖阻滞和凋亡，而不会对正常人CD34（+）祖细胞产生细胞毒活性。引人注目的是，GLS1敲除显著抑制NSG小鼠AML的发展。CB-839的抗白血病活性被高活性GAC（K320A）等位基因的表达和三羧酸循环产物α -酮戊二酸酯的添加所抵消，表明GLS1在AML细胞存活中的关键功能。最后，谷氨酰胺解抑制激活线粒体凋亡，并协同使白血病细胞对BCL-2抑制剂ABT-199的启动敏感。这些发现表明，通过GLS1抑制靶向谷氨酰胺成瘾为AML提供了一种潜在的新治疗策略。
Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acutemyeloid leukemia (AML) cells. Glutaminase C (GAC) is the GAisoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product alpha-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.