Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia.
Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia.
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DOI：
10.1186/s13045-020-00973-4
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发表时间：
2020-10-19
影响因子：
28.5
通讯作者：
Blachly JS
中科院分区：
文献类型：
--
作者：
Brinton LT;Zhang P;Williams K;Canfield D;Orwick S;Sher S;Wasmuth R;Beaver L;Cempre C;Skinner J;Cannon M;Govande M;Harrington B;Lehman A;Byrd JC;Lapalombella R;Blachly JS
急性髓性白血病（AML）是一种异质性和复杂的疾病，对这种疾病的治疗对大多数患者都没有治愈性。在年轻患者中，FLT 3的内部串联重复（FLT 3-ITD）是一种常见的突变，临床上批准了两种对FLT 3具有不同效力和特异性的抑制剂（米多鲁肽和gilteritinib）。然而，AML患者的高复发率或失败的初始响应表明，添加第二种靶向治疗可能是提高疗效所必需的。使用无偏见的大规模CRISPR筛选，我们在遗传上鉴定了BCL 2敲除与批准的FLT 3抑制剂具有协同效应。在这里，我们提供了支持性研究，验证了FLT 3抑制剂与维奈托克联合在体外和体内对FLT 3-ITD驱动的AML的多种模型的治疗潜力。我们的无偏方法为共同靶向FLT 3和BCL 2提供了遗传验证，并重新利用CRISPR筛选数据，利用全基因组范围进行机制理解。
Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
20.3
作者：
Thiede, C;Steudel, C;Illmer, T
通讯作者：
Illmer, T
影响因子：
--
作者：
Grundy, Martin;Balakrishnan, Sahana;Russell, Nigel H
通讯作者：
Russell, Nigel H
Gilteritinib对复发或难治性急性髓样白血病对FLT3的选择性抑制：一种多中心，人类，开放标签，第1-2期研究。
DOI：
10.1016/s1470-2045(17)30416-3
发表时间：
2017-08
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Perl AE;Altman JK;Cortes J;Smith C;Litzow M;Baer MR;Claxton D;Erba HP;Gill S;Goldberg S;Jurcic JG;Larson RA;Liu C;Ritchie E;Schiller G;Spira AI;Strickland SA;Tibes R;Ustun C;Wang ES;Stuart R;Röllig C;Neubauer A;Martinelli G;Bahceci E;Levis M
通讯作者：
Levis M
影响因子：
50.3
作者：
Shih AH;Jiang Y;Meydan C;Shank K;Pandey S;Barreyro L;Antony-Debre I;Viale A;Socci N;Sun Y;Robertson A;Cavatore M;de Stanchina E;Hricik T;Rapaport F;Woods B;Wei C;Hatlen M;Baljevic M;Nimer SD;Tallman M;Paietta E;Cimmino L;Aifantis I;Steidl U;Mason C;Melnick A;Levine RL
通讯作者：
Levine RL