Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.
Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.
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DOI：
10.1242/dmm.049088
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发表时间：
2022-05-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
RAS突变发生在广谱的人类造血系统恶性肿瘤中。激活血细胞中的Ras突变导致小鼠的造血系统恶性肿瘤。在鼠造血干细胞（HSC）中，突变型N-RasG 12 D激活Stat 5以失调干细胞功能。然而，根本的机制仍然难以捉摸。在这项研究中，我们证明了由过度活跃的Nras突变体G12 D诱导的Stat 5激活依赖于Jak 2活性。Jak 2在Nras突变型HSC和祖细胞（HSPC）中被激活，用鲁索替尼抑制Jak 2可显著降低NrasG 12 D小鼠体内的Stat 5激活和HSPC过度增殖。Jak 2-Stat 5的激活与Jak 2/Stat 5的抑制性效应子Socs 2的下调相关。Socs 2的恢复阻断了骨髓移植受体中的NrasG 12 D HSC重建。在携带RAS突变的人急性髓性白血病（AML）细胞中也观察到SOCS 2下调。RAS突变AML细胞表现出在SOCS 2基因座处的增强子活性标记H3 K27 ac的抑制。最后，RAS突变AML细胞中SOCS 2的恢复减轻了白血病生长。因此，我们发现了一种新的信号反馈回路，其中过度活跃的Ras信号通过抑制Socs 2激活Jak 2/Stat 5。Jak 2/Stat 5通常被认为与Ras信号传导平行或上游。我们已经发现了一种新的信号反馈回路，其中过度活跃的Ras信号通过抑制Socs 2激活Jak 2/Stat 5。
RAS mutations occur in a broad spectrum of human hematopoietic malignancies. Activating Ras mutations in blood cells leads to hematopoietic malignancies in mice. In murine hematopoietic stem cells (HSCs), mutant N-RasG12D activates Stat5 to dysregulate stem cell function. However, the underlying mechanism remains elusive. In this study, we demonstrate that Stat5 activation induced by a hyperactive Nras mutant, G12D, is dependent on Jak2 activity. Jak2 is activated in Nras mutant HSCs and progenitors (HSPCs), and inhibiting Jak2 with ruxolitinib significantly decreases Stat5 activation and HSPC hyper-proliferation in vivo in NrasG12D mice. Activation of Jak2-Stat5 is associated with downregulation of Socs2, an inhibitory effector of Jak2/Stat5. Restoration of Socs2 blocks NrasG12D HSC reconstitution in bone marrow transplant recipients. SOCS2 downregulation is also observed in human acute myeloid leukemia (AML) cells that carry RAS mutations. RAS mutant AML cells exhibited suppression of the enhancer active marker H3K27ac at the SOCS2 locus. Finally, restoration of SOCS2 in RAS mutant AML cells mitigated leukemic growth. Thus, we discovered a novel signaling feedback loop whereby hyperactive Ras signaling activates Jak2/Stat5 via suppression of Socs2. Summary: Jak2/Stat5 is often considered to be parallel to or upstream of Ras signaling. We have discovered a novel signaling feedback loop whereby hyperactive Ras signaling activates Jak2/Stat5 via suppression of Socs2.
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影响因子：
10.1
作者：
Ross DM;Babon JJ;Tvorogov D;Thomas D
通讯作者：
Thomas D
影响因子：
--
作者：
Jatiani SS;Baker SJ;Silverman LR;Reddy EP
通讯作者：
Reddy EP
影响因子：
11.4
作者：
Hansen, N.;Agerstam, H.;Wahlestedt, M.;Landberg, N.;Askmyr, M.;Ehinger, M.;Rissler, M.;Lilljebjorn, H.;Johnels, P.;Ishiko, J.;Melo, J. V.;Alexander, W. S.;Bryder, D.;Jaras, M.;Fioretos, T.
通讯作者：
Fioretos, T.
影响因子：
11.4
作者：
Puigdecanet, E.;Espinet, B.;Florensa, L.
通讯作者：
Florensa, L.
影响因子：
5.2
作者：
Akada, Hajime;Akada, Saeko;Hutchison, Robert E.;Sakamoto, Kazuhito;Wagner, Kay-Uwe;Mohi, Golam
通讯作者：
Mohi, Golam