Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.
Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.
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DOI：
10.1038/s41375-022-01554-9
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Williams, Owen
中科院分区：
文献类型：
--
作者：
Clesham, Katherine;Walf-Vorderwulbecke, Vanessa;Gasparoli, Luca;Virely, Clemence;Cantilena, Sandra;Tsakaneli, Alexia;Inglott, Sarah;Adams, Stuart;Samarasinghe, Sujith;Bartram, Jack;Williams, Gareth;de Boer, Jasper;Williams, Owen
很大一部分患有急性髓性白血病（AML）的患者不能通过常规化疗治愈，复发性疾病是常见的问题。分子靶向的基本致癌介质是一个有吸引力的方法，以改善这种疾病的结果。造血转录因子c-MYB已被揭示为维持AML中异常基因表达程序的复合物的中心组分。我们之前已经筛选了连接图数据库，以确定甲苯咪唑作为靶向c-MYB的抗AML治疗剂。在本研究中，我们证明了该筛选的另一个命中，甾体内酯withaferin A（WFA），诱导c-MYB蛋白的快速消融和随后的c-MYB靶基因表达抑制，白血病细胞活力丧失，集落形成减少和疾病进展受损。虽然WFA已被报道具有多效性抗癌作用，但我们证明其抗AML活性取决于c-MYB调节，并且可以通过稳定的c-MYB突变体部分逆转。c-MYB消融是由于WFA诱导蛋白毒性和未折叠蛋白应答后，白血病细胞中HSP/HSC 70伴侣蛋白稳态被破坏所致。WFA在世界各地的传统药物中的广泛使用表明，它是一种很有前途的候选药物，可用于AML治疗。
A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, we demonstrate that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines throughout the world indicates that it represents a promising candidate for repurposing into AML therapy.
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影响因子：
3.7
作者：
Coulibaly A;Haas A;Steinmann S;Jakobs A;Schmidt TJ;Klempnauer KH
通讯作者：
Klempnauer KH
DOI：
10.1073/pnas.88.6.2351
发表时间：
1991-03-01
影响因子：
11.1
作者：
CALABRETTA, B;SIMS, RB;GEWIRTZ, AM
通讯作者：
GEWIRTZ, AM
影响因子：
16
作者：
Leu, J. I-Ju;Pimkina, Julia;Frank, Amanda;Murphy, Maureen E.;George, Donna L.
通讯作者：
George, Donna L.
DOI：
10.1158/1541-7786.mcr-11-0019
发表时间：
2011-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Leu JI;Pimkina J;Pandey P;Murphy ME;George DL
通讯作者：
George DL
影响因子：
1.8
作者：
Dai, Tianming;Jiang, Weifan;Dai, Renke
通讯作者：
Dai, Renke