AKT activation is a feature of CALR mutant myeloproliferative neoplasms.
AKT activation is a feature of CALR mutant myeloproliferative neoplasms.
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DOI：
10.1038/s41375-018-0224-8
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Xu K
中科院分区：
文献类型：
--
作者：
Fu C;Wen QJ;Marinaccio C;Ling T;Chen W;Bulic M;Lasho T;Tefferi A;Crispino JD;Xu K
在MPN中的驱动突变中，CALR突变激活JAK/STAT信号传导的机制是独特的，因为CALR突变蛋白的新C末端直接结合MPL，导致组成性激活[1，2]。CALR突变体也被证明可以激活MAPK通路[3]。CALR突变体是否进一步激活PI 3 K/AKT信号传导是有争议的，有几项研究报告缺乏（或适度）激活[2，4]，但另一项研究证明了有效的激活[5]。前一项研究依赖于用CALR突变等位基因转导Ba/F3 TpoR细胞，而后者在具有巨核细胞潜能的细胞系中探索途径。此外，PI 3 K/AKT信号传导在多大程度上是CALR突变型MPN中的靶标一直存在争议，至少有一项研究报告该途径的抑制剂不与鲁索利替尼协同作用[2]。为了解决这一差异，我们在多种情况下测定了JAK/STAT和AKT的活化。首先，我们在原代鼠c-kit+骨髓祖细胞中过表达CALR 1型（del 52）和2型（ins 5）突变体，并将细胞培养48小时。我们观察到STAT 5和AKT的激活增强（图1a）。接下来，我们将用CALRdel 52突变体或空载体转导的骨髓移植到辐射的受体小鼠中并评估AKT活化。脾细胞的细胞内流动和蛋白质印迹均显示p-AKT增加（图1A和1B）。第1b、c段）。最后，我们分析了总的和磷酸-
Among the driver mutations in the MPNs, the mechanism by which CALR mutations activate JAK/STAT signaling is unique in that the novel C-terminus of CALR mutant proteins binds directly to MPL leading to constitutive activation [1, 2]. CALR mutants have also been shown to activate the MAPK pathway [3]. Whether CALR mutants further activate PI3K/AKT signaling is controversial, with several studies reporting a lack of (or modest) activation [2, 4], but another demonstrating potent activation [5]. The former studies relied upon transduction of Ba/F3 TpoR cells with CALR mutant alleles whereas the latter probed the pathway in cells lines with megakaryocytic potential. Moreover, the extent to which PI3K/AKT signaling is a target in CALR mutant MPNs has been debated, with at least one study reporting that inhibitors of this pathway do not synergize with ruxolitinib [2].To address the discrepancy, we assayed for activation of JAK/STAT and AKT in multiple settings. First, we overexpressed the CALR type 1 (del52) and type 2 (ins5) mutants in primary murine c-kit+ bone marrow progenitors and cultured the cells for 48h. We observed enhanced activation of both STAT5 and AKT (Fig. 1a). Next we transplanted bone marrow transduced with CALRdel52 mutant or empty vector to irradiated recipient mice and assessed AKT activation. Both intracellular flow and western blots of spleen cells revealed increase in p-AKT (Figs. 1b, c). Finally, we assayed for total and phospho-
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影响因子：
28.2
作者：
Elf S;Abdelfattah NS;Chen E;Perales-Patón J;Rosen EA;Ko A;Peisker F;Florescu N;Giannini S;Wolach O;Morgan EA;Tothova Z;Losman JA;Schneider RK;Al-Shahrour F;Mullally A
通讯作者：
Mullally A
影响因子：
11.4
作者：
Kollmann K;Warsch W;Gonzalez-Arias C;Nice FL;Avezov E;Milburn J;Li J;Dimitropoulou D;Biddie S;Wang M;Poynton E;Colzani M;Tijssen MR;Anand S;McDermott U;Huntly B;Green T
通讯作者：
Green T
影响因子：
12.8
作者：
Pardanani A;Tefferi A
通讯作者：
Tefferi A
影响因子：
20.3
作者：
Chachoua, Ilyas;Pecquet, Christian;Constantinescu, Stefan N.
通讯作者：
Constantinescu, Stefan N.
影响因子：
20.3
作者：
Marty, Caroline;Pecquet, Christian;Vainchenker, William
通讯作者：
Vainchenker, William