A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.
A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.
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加强FLT3-ITD AML治疗的联合治疗方法。
DOI：
10.1016/j.xcrm.2023.101286
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发表时间：
2023-11-21
影响因子：
14.3
通讯作者：
Liang, Aibin
中科院分区：
文献类型：
--
作者：
Long, Jun;Chen, Xinjie;Shen, Yan;Lei, Yichen;Mu, Lili;Wang, Zhen;Xiang, Rufang;Gao, Wenhui;Wang, Lining;Wang, Ling;Jiang, Jieling;Zhang, Wenjun;Lu, Huina;Dong, Yan;Ding, Yi;Zhu, Honghu;Hong, Dengli;Sun, Yi Eve;Hu, Jiong;Liang, Aibin
fms样酪氨酸激酶-3 （FLT3-ITDs）的内部串联重复突变发生在25%-30%的急性髓性白血病（AML）患者中，并与预后不良相关。尽管FLT3抑制剂已经显示出初步的临床疗效，但FLT3- itd AML患者的总体预后仍然很差，这凸显了开发更有效治疗策略的紧迫性。在本研究中，我们发现FLT3抑制剂降低了抗癌蛋白p53的蛋白稳定性，导致耐药。用蛋白酶体抑制剂阻断p53降解可恢复细胞内p53蛋白水平，并与FLT3-ITD抑制剂联合使用，在细胞、小鼠模型和患者中对FLT3-ITD AML显示出优越的治疗效果。这些数据表明，这种联合治疗方法可能是针对FLT3-ITD AML的一种有希望的策略。FLT3抑制下调FLT3- itd AML中p53蛋白促进耐药FLT3- itd下游MYC/USP10信号调节p53稳定性蛋白酶体抑制剂恢复p53蛋白减轻对FLT3抑制剂的耐药双药策略对复发/难治性FLT3- itd AML有效Long等发现FLT3抑制通过MYC/USP10信号诱导p53泛素化和蛋白酶体降解，导致耐药。蛋白酶体抑制剂恢复p53蛋白，并与FLT3抑制剂共同消除FLT3- itd AML。FLT3 +蛋白酶体抑制剂的挽救治疗对复发/难治性FLT3- itd AML患者显示出非凡的治疗效果。
Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%–30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML. FLT3 inhibition downregulates p53 protein in FLT3-ITD AML to promote drug resistance MYC/USP10 signaling downstream of FLT3-ITD regulates p53 stability Proteasome inhibitors restore p53 protein to alleviate resistance to FLT3 inhibitors Dual-drug strategy is efficacious in treating relapsed/refractory FLT3-ITD AML Long et al. find that FLT3 inhibition induces p53 ubiquitination and proteasomal degradation through MYC/USP10 signaling, leading to drug resistance. Proteasome inhibitor restores p53 protein and corroborates with FLT3 inhibitor to eliminate FLT3-ITD AML. Salvage therapy with FLT3 plus proteasome inhibitors shows extraordinary therapeutic efficacy in patients with relapsed/refractory FLT3-ITD AML.
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影响因子：
64.8
作者：
Tyner JW;Tognon CE;Bottomly D;Wilmot B;Kurtz SE;Savage SL;Long N;Schultz AR;Traer E;Abel M;Agarwal A;Blucher A;Borate U;Bryant J;Burke R;Carlos A;Carpenter R;Carroll J;Chang BH;Coblentz C;d'Almeida A;Cook R;Danilov A;Dao KT;Degnin M;Devine D;Dibb J;Edwards DK 5th;Eide CA;English I;Glover J;Henson R;Ho H;Jemal A;Johnson K;Johnson R;Junio B;Kaempf A;Leonard J;Lin C;Liu SQ;Lo P;Loriaux MM;Luty S;Macey T;MacManiman J;Martinez J;Mori M;Nelson D;Nichols C;Peters J;Ramsdill J;Rofelty A;Schuff R;Searles R;Segerdell E;Smith RL;Spurgeon SE;Sweeney T;Thapa A;Visser C;Wagner J;Watanabe-Smith K;Werth K;Wolf J;White L;Yates A;Zhang H;Cogle CR;Collins RH;Connolly DC;Deininger MW;Drusbosky L;Hourigan CS;Jordan CT;Kropf P;Lin TL;Martinez ME;Medeiros BC;Pallapati RR;Pollyea DA;Swords RT;Watts JM;Weir SJ;Wiest DL;Winters RM;McWeeney SK;Druker BJ
通讯作者：
Druker BJ
影响因子：
64.5
作者：
Liang K;Smith ER;Aoi Y;Stoltz KL;Katagi H;Woodfin AR;Rendleman EJ;Marshall SA;Murray DC;Wang L;Ozark PA;Mishra RK;Hashizume R;Schiltz GE;Shilatifard A
通讯作者：
Shilatifard A
Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平。
影响因子：
64.5
作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
通讯作者：
Yuan J
影响因子：
20.3
作者：
Prokocimer, Miron;Molchadsky, Alina;Rotter, Varda
通讯作者：
Rotter, Varda
影响因子：
20.3
作者：
Steensma, David P.;Bejar, Rafael;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.