BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
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DOI：
10.1038/nature24294
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发表时间：
2017-11-16
期刊：
影响因子：
64.8
通讯作者：
Trumpp, Andreas
中科院分区：
文献类型：
--
作者：
Raffel, Simon;Falcone, Mattia;Trumpp, Andreas
最近发现支链氨基酸 (BCAA) 途径和高水平的 BCAA 转氨酶 1 (BCAT1) 与多种癌症实体的侵袭性相关 (1-6)。然而，BCAT1 在此过程中的机制作用仍然很大程度上不确定。在这里，通过对人类急性髓系白血病 (AML) 干细胞和非干细胞群体进行高分辨率蛋白质组学分析，我们发现白血病干细胞中 BCAA 途径富集，并且 BCAT1 蛋白和转录本过表达。我们发现，BCAT1 将 a-氨基从 BCAA 转移到 α-酮戊二酸 (alpha KG)，是细胞内 aKG 稳态的关键调节因子。除了在三羧酸循环中的作用之外，α KG 也是 α KG 依赖性双加氧酶的重要辅助因子，例如 Egl-9 家族缺氧诱导因子 1 (EGLN1) 和 DNA 脱甲基酶的 10-11 易位 (TET) 家族 (7-10)。白血病细胞中 BCAT1 的敲低导致 aKG 积累，导致 EGLN1 介导的 HIF1 α 蛋白降解。这导致了生长和生存缺陷，并消除了引发白血病的潜力。相比之下，白血病细胞中 BCAT1 的过度表达会降低细胞内 α KG 水平，并通过改变 TET 活性导致 DNA 高甲基化。具有高水平 BCAT1 (BCAT1(high)) 的 AML 表现出与携带突变异柠檬酸脱氢酶 (IDHmut) 的病例相似的 DNA 高甲基化表型，其中 TET2 受到致癌代谢物 2-羟基戊二酸的抑制 (11,12)。高水平的 BCAT1 与 IDH(WT)TET2(WT) 患者的总生存期较短密切相关，但与 IDHmut 或 TET2(mut) AML 无关。 IDHmut AML(13) 特征性基因集在 IDH(WT)TET2(WT)BCAT1(high) 状态患者的样本中得到富集。 BCAT1（高）AML 显示出白血病干细胞特征的强劲富集 (14,15)，配对样本分析显示疾病复发时 BCAT1 水平显着增加。总之，通过限制细胞内 α KG，BCAT1 将 BCAA 分解代谢与 HIF1 α 稳定性和表观基因组景观的调节联系起来，模仿 IDH 突变的影响。我们的结果表明 BCAA-BCAT1-α KG 通路可作为损害 IDH(WT)TET2(WT) AML 患者白血病干细胞功能的治疗靶点。
The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities(1-6). However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers a-amino groups from BCAAs to alpha-ketoglutarate (alpha KG), is a critical regulator of intracellular aKG homeostasis. Further to its role in the tricarboxylic acid cycle, alpha KG is an essential cofactor for alpha KG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases(7-10). Knockdown of BCAT1 in leukaemia cells caused accumulation of aKG, leading to EGLN1-mediated HIF1 alpha protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular alpha KG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1(high)) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate(11,12). High levels of BCAT1 strongly correlate with shorter overall survival in IDH(WT)TET2(WT), but not IDHmut or TET2(mut) AML. Gene sets characteristic for IDHmut AML(13) were enriched in samples from patients with an IDH(WT)TET2(WT)BCAT1(high) status. BCAT1(high) AML showed robust enrichment for leukaemia stem-cell signatures(14,15), and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular alpha KG, BCAT1 links BCAA catabolism to HIF1 alpha stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-alpha KG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDH(WT)TET2(WT) AML.