Downregulating Notch counteracts Kras(G12D)-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.
Downregulating Notch counteracts Kras(G12D)-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.
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下调Notch可抵消Kras(G12D)诱导的骨髓增殖性肿瘤中的ERK激活和氧化磷酸化。
DOI：
10.1038/s41375-018-0248-0
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发表时间：
2019-03
期刊：
影响因子：
11.4
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Kong G;You X;Wen Z;Chang YI;Qian S;Ranheim EA;Letson C;Zhang X;Zhou Y;Liu Y;Rajagopalan A;Zhang J;Stieglitz E;Loh M;Hofmann I;Yang D;Zhong X;Padron E;Zhou L;Pear WS;Zhang J
Notch信号通路有助于广泛的人类癌症（包括造血恶性肿瘤）的发病机理。它的功能高度取决于特定的细胞环境。在人T细胞白血病中，功能notch1突变普遍存在，而髓样白血病中的Notch信号丧失。在这里，我们报告了Notch信号传导在致癌性KRAS诱导的脊髓增生性肿瘤（MPN）中的新型致癌功能。我们发现，通过DNMAML表达或POFUT1缺失在造血细胞中的Notch信号下调可显着阻止KRASG12D小鼠的MPN发育，以细胞自主的方式阻止。进一步的机械研究表明，抑制Notch信号传导显着上调DUSP1，DUSP1是一种使P-ERK失活的双磷酸酶，并下调了KRASG12D细胞中细胞因子诱发的ERK激活。此外，在KRASG12D细胞中，线粒体代谢大大增强，但在对照细胞中，DNMAML显着重新编程。因此，在KRASG12D小鼠中的细胞增殖和髓样室扩大显着降低。与这些发现一致，联合抑制MEK/ERK途径和线粒体氧化磷酸化有效地抑制了人类和小鼠白血病细胞的体外生长。我们的研究为靶向ERK信号传导和异常代谢提供了强烈的合理性。
The Notch signaling pathway contributes to the pathogenesis of a wide spectrum of human cancers, including hematopoietic malignancies. Its functions are highly dependent on the specific cellular context. Gain-of-function NOTCH1 mutations are prevalent in human T cell leukemia, while loss of Notch signaling is reported in myeloid leukemias. Here, we report a novel oncogenic function of Notch signaling in oncogenic Kras-induced myeloproliferative neoplasm (MPN). We find that downregulation of Notch signaling in hematopoietic cells via DNMAML expression or Pofut1 deletion significantly blocks MPN development in KrasG12D mice in a cell-autonomous manner. Further mechanistic studies indicate that inhibition of Notch signaling significantly upregulates Dusp1, a dual phosphatase that inactivates p-ERK, and downregulates cytokine-evoked ERK activation in KrasG12D cells. Moreover, mitochondrial metabolism is greatly enhanced in KrasG12D cells but significantly reprogrammed by DNMAML close to that in control cells. Consequently, cell proliferation and expanded myeloid compartment in KrasG12D mice are significantly reduced. Consistent with these findings, combined inhibition of the MEK/ERK pathway and mitochondrial oxidative phosphorylation effectively inhibited the growth of human and mouse leukemia cells in vitro. Our study provides a strong rational to target both ERK signaling and aberrant metabolism in oncogenic Ras-driven myeloid leukemia.
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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.
DOI：
10.1084/jem.20121484
发表时间：
2013-02-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lobry C;Ntziachristos P;Ndiaye-Lobry D;Oh P;Cimmino L;Zhu N;Araldi E;Hu W;Freund J;Abdel-Wahab O;Ibrahim S;Skokos D;Armstrong SA;Levine RL;Park CY;Aifantis I
通讯作者：
Aifantis I
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
5.3
作者：
KIDD, S;KELLEY, MR;YOUNG, MW
通讯作者：
YOUNG, MW
DOI：
10.1084/jem.20121527
发表时间：
2013-02-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kannan S;Sutphin RM;Hall MG;Golfman LS;Fang W;Nolo RM;Akers LJ;Hammitt RA;McMurray JS;Kornblau SM;Melnick AM;Figueroa ME;Zweidler-McKay PA
通讯作者：
Zweidler-McKay PA