Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute lymphoblastic leukemia.
Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute lymphoblastic leukemia.
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PI 3 K/AKT/MTOR信号通路在B前体急性淋巴细胞白血病靶向治疗中的功能表征
DOI：
10.1038/s41417-022-00491-0
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发表时间：
2022-11
影响因子：
6.4
通讯作者：
Duque-Afonso, Jesus
中科院分区：
文献类型：
--
作者：
Grueninger, Patricia K.;Uhl, Franziska;Herzog, Heike;Gentile, Gaia;Andrade-Martinez, Marta;Schmidt, Tobias;Han, Kyuho;Morgens, David W.;Bassik, Michael C.;Cleary, Michael L.;Gorka, Oliver;Zeiser, Robert;Gross, Olaf;Duque-Afonso, Jesus
b细胞前体急性淋巴细胞白血病（B-ALL）以信号通路激活为特征，参与白血病细胞的生存和增殖。研究人员利用无偏shRNA文库筛选了靶向信号通路，发现MTOR是人B-ALL E2A-PBX1+ RCH-ACV细胞依赖的关键基因。利用遗传学和药理学方法，我们研究了B-ALL细胞是否依赖于MTOR上游信号通路，包括PI3K/AKT和MTORC1或MTORC2复合物，在体外和体内进行增殖和存活。值得注意的是，MTOR和AKT的联合抑制对不同核型B-ALL细胞增殖的抑制具有协同作用。因此，在遗传分析中，B-ALL细胞更依赖于MTORC2而不是MTORC1复合物。利用细胞代谢组学，我们确定了shrna介导的MTOR敲低或药物抑制后线粒体燃料氧化的变化。在抑制MTOR和相关的上游信号通路后，细胞对脂肪酸代谢产生能量的依赖性增加，揭示了联合治疗的可能靶点。综上所述，B-ALL依赖于PI3K/AKT/MTOR信号通路，靶向该通路的特异性小分子联合治疗B-ALL患者似乎很有希望。
B-cell precursor acute lymphoblastic leukemias (B-ALL) are characterized by the activation of signaling pathways, which are involved in survival and proliferation of leukemia cells. Using an unbiased shRNA library screen enriched for targeting signaling pathways, we identified MTOR as the key gene on which human B-ALL E2A-PBX1+ RCH-ACV cells are dependent. Using genetic and pharmacologic approaches, we investigated whether B-ALL cells depend on MTOR upstream signaling pathways including PI3K/AKT and the complexes MTORC1 or MTORC2 for proliferation and survival in vitro and in vivo. Notably, the combined inhibition of MTOR and AKT shows a synergistic effect on decreased cell proliferation in B-ALL with different karyotypes. Hence, B-ALL cells were more dependent on MTORC2 rather than MTORC1 complex in genetic assays. Using cell metabolomics, we identified changes in mitochondrial fuel oxidation after shRNA-mediated knockdown or pharmacological inhibition of MTOR. Dependence of the cells on fatty acid metabolism for their energy production was increased upon inhibition of MTOR and associated upstream signaling pathways, disclosing a possible target for a combination therapy. In conclusion, B-ALL are dependent on the PI3K/AKT/MTOR signaling pathway and the combination of specific small molecules targeting this pathway appears to be promising for the treatment of B-ALL patients.
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影响因子：
16
作者：
Kim, DH;Sarbassov, DD;Sabatini, DM
通讯作者：
Sabatini, DM
影响因子：
46.9
作者：
Morgens DW;Deans RM;Li A;Bassik MC
通讯作者：
Bassik MC
影响因子：
50.3
作者：
Geng H;Hurtz C;Lenz KB;Chen Z;Baumjohann D;Thompson S;Goloviznina NA;Chen WY;Huan J;LaTocha D;Ballabio E;Xiao G;Lee JW;Deucher A;Qi Z;Park E;Huang C;Nahar R;Kweon SM;Shojaee S;Chan LN;Yu J;Kornblau SM;Bijl JJ;Ye BH;Ansel KM;Paietta E;Melnick A;Hunger SP;Kurre P;Tyner JW;Loh ML;Roeder RG;Druker BJ;Burger JA;Milne TA;Chang BH;Müschen M
通讯作者：
Müschen M
影响因子：
4.7
作者：
Bernt KM;Hunger SP
通讯作者：
Hunger SP
影响因子：
3.2
作者：
Morishita, Naoto;Tsukahara, Hirokazu;Morishima, Tsuneo
通讯作者：
Morishima, Tsuneo