The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia.
The KRAS-G12D mutation induces metabolic vulnerability in B-cell acute lymphoblastic leukemia.
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KRAS-G12D 突变导致 B 细胞急性淋巴细胞白血病代谢脆弱性
DOI：
10.1016/j.isci.2022.103881
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发表时间：
2022-03-18
期刊：
影响因子：
5.8
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Xu Y;Fang H;Chen Y;Tang Y;Sun H;Kong Z;Yang F;Kirschner-Schwabe R;Zhu L;Toker A;Xiao N;Zhou BS;Li H
RAS 通路基因突变在急性淋巴细胞白血病 (ALL) 中非常普遍。然而，RAS 突变对 ALL 细胞生长的影响尚未得到实验表征，并且正在寻求有效的 RAS 靶向疗法。在这里，我们发现携带 KRAS-G12D 突变的 Reh ALL 细胞在体外表现出增殖率增加，但在小鼠体内表现出严重的生长受损。为了探索这种差异，对多个 ALL 细胞系进行的增殖测定表明，KRAS-G12D 重新连接了蛋氨酸和精氨酸代谢。同位素示踪结果表明，KRAS-G12D 促进蛋氨酸和精氨酸的分解代谢，分别支持多胺和脯氨酸的合成代谢。多胺生物合成的化学抑制选择性杀死 KRAS-G12D B-ALL 细胞。最后，化学抑制 AKT/mTOR 信号传导消除了氨基酸代谢的改变，并强烈促进 B-ALL 异种移植物中 KRAS-G12D 细胞的体内生长。因此，我们的研究说明了过度激活的 AKT/mTOR 信号传导如何对血液恶性肿瘤与实体瘤产生不同的影响。携带 KRAS-G12D 的 Reh ALL 细胞在小鼠中表现出生长受损 KRAS-G12D 重新连接 B-ALL 细胞中的蛋氨酸和精氨酸代谢化学抑制多胺生物合成可以有效杀死 KRAS-G12D ALL 细胞适度的 mTOR 抑制可以挽救 KRAS-G12D B-ALL 细胞的体内生长生物化学；分子生物学
Mutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation rates in vitro but displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted the in vivo growth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors. Reh ALL cells bearing KRAS-G12D displayed compromised growth in mice KRAS-G12D rewires methionine and arginine metabolism in B-ALL cells Chemically inhibiting polyamine biosynthesis can potently kill KRAS-G12D ALL cells Moderate mTOR inhibition can rescue in vivo growth of KRAS-G12D B-ALL cells Biological sciences; Biochemistry; Molecular biology
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
3.5
作者：
Li, Hui;Meininger, Cynthia J.;Wu, Guoyao
通讯作者：
Wu, Guoyao
影响因子：
13.8
作者：
Longo VD;Fontana L
通讯作者：
Fontana L
DOI：
10.1038/s41568-018-0050-3
发表时间：
2018-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Casero RA Jr;Murray Stewart T;Pegg AE
通讯作者：
Pegg AE
影响因子：
13.8
作者：
Bryant, Kirsten L.;Mancias, Joseph D.;Kimmelman, Alec C.;Der, Channing J.
通讯作者：
Der, Channing J.