Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.
Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.
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DOI：
10.1126/sciadv.abc7120
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发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Birsoy K
中科院分区：
文献类型：
--
作者：
Guarecuco R;Williams RT;Baudrier L;La K;Passarelli MC;Ekizoglu N;Mestanoglu M;Alwaseem H;Rostandy B;Fidelin J;Garcia-Bermudez J;Molina H;Birsoy K
血浆硫胺素浓度影响缺乏硫胺素摄取的白血病细胞对左旋门冬酰胺酶的敏感性。肿瘤环境影响抗癌治疗反应，但细胞外营养物质影响药物敏感性在很大程度上是未知的。使用功能基因组学，我们确定修饰的l-天冬酰胺酶（ASNase）的反应，并确定硫胺素焦磷酸激酶1作为一个代谢依赖ASNase治疗。虽然硫胺素通常不限制细胞增殖，但DNA条形码竞争测定鉴定了在低硫胺素下生长次优并且特征在于溶质载体家族19成员2（SLC 19 A2）（硫胺素转运蛋白）的低表达的白血病细胞系。当标准培养基硫胺素浓度降低至人血浆浓度的约100倍时，SLC 19 A2是最佳生长和ASNase抗性所必需的。此外，通过饮食使小鼠的血液硫胺素含量人源化可使SLC 19 A2-低白血病细胞在体内对ASNase敏感。总之，我们的工作表明，硫胺素的利用是一些癌细胞的ASNase反应的决定因素，过量供应维生素可能会影响白血病的治疗反应。
Plasma thiamine concentrations affect l-asparaginase sensitivity of leukemia cells deficient for thiamine uptake. Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered ~100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
11.2
作者：
Ehsanipour EA;Sheng X;Behan JW;Wang X;Butturini A;Avramis VI;Mittelman SD
通讯作者：
Mittelman SD
影响因子：
6.4
作者：
Bairati, Isabelle;Meyer, Francois;Tetu, Bernard
通讯作者：
Tetu, Bernard
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
7.7
作者：
Muir, Alexander;Danai, Laura V.;Heidan, Mathew G. Vander
通讯作者：
Heidan, Mathew G. Vander