AKT is a therapeutic target in myeloproliferative neoplasms.
AKT is a therapeutic target in myeloproliferative neoplasms.
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AKT 是骨髓增生性肿瘤的治疗靶点
作者：
大多数BCR-ABL 1阴性骨髓增生性肿瘤（MPN）患者存在JAK 2或MPL突变，导致JAK/STAT、PI 3 K和ERK信号通路的组成性激活。JAK抑制剂本身不足以在MPN中产生选择性克隆抑制，并且与造血毒性相关。MK-2206是一种强效变构AKT抑制剂，在一项实体瘤I期研究中耐受性良好，无骨髓抑制证据。在此，我们发现MK-2206对PI 3 K/AKT信号传导的抑制通过减少AKT的磷酸化和抑制其下游信号分子来影响JAK 2 V617 F-或MPLW 515 L-表达细胞的生长。此外，我们证明MK-2206与ruxolitinib在抑制JAK 2 V617 F突变型SET 2细胞的生长方面具有协同作用。重要的是，MK-2206可抑制原发性骨髓纤维化患者的造血祖细胞集落形成，缓解MPLW 515 L诱导的MPN小鼠的肝脾肿大并降低骨髓、肝脏和脾脏中的巨核细胞负荷。总之，这些发现确立了AKT作为MPN的合理治疗靶点。
The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F-or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.
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影响因子：
20.3
作者：
Guglielmelli, Paola;Barosi, Giovanni;Vannucchi, Alessandro M.
通讯作者：
Vannucchi, Alessandro M.
DOI：
10.1158/1078-0432.ccr-11-1541
发表时间：
2011-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Fiskus W;Verstovsek S;Manshouri T;Rao R;Balusu R;Venkannagari S;Rao NN;Ha K;Smith JE;Hembruff SL;Abhyankar S;McGuirk J;Bhalla KN
通讯作者：
Bhalla KN
影响因子：
11.4
作者：
Guerini, V.;Barbui, V.;Rambaldi, A.
通讯作者：
Rambaldi, A.
影响因子：
20.3
作者：
Akada, Hajime;Yan, Dongqing;Mohi, M. Golam
通讯作者：
Mohi, M. Golam
影响因子：
5.7
作者：
Fiskus, Warren;Verstovsek, Srdan;Bhalla, Kapil N.
通讯作者：
Bhalla, Kapil N.