Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Dis Model Mech. 2022 May 1;15(5). doi: 10.1242/dmm.049088. Epub 2022 May 6.
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.
RAS 突变发生在广泛的人类造血恶性肿瘤中。在血细胞中激活 Ras 突变会导致小鼠发生造血恶性肿瘤。在鼠造血干细胞（HSCs）中，突变 N-RasG12D 激活 Stat5 以扰乱干细胞功能。然而，其潜在机制仍不清楚。在这项研究中，我们证明了由高活性 Nras 突变体 G12D 诱导的 Stat5 激活依赖于 Jak2 活性。Jak2 在 Nras 突变 HSCs 和祖细胞（HSPCs）中被激活，用鲁索替尼抑制 Jak2 可显著降低 NrasG12D 小鼠体内 Stat5 激活和 HSPC 过度增殖。Jak2-Stat5 的激活与 Sos2 的下调有关，Sos2 是 Jak2/Stat5 的抑制效应物。Socs2 的恢复可阻止 NrasG12D HSC 在骨髓移植受者中的重建。在携带 RAS 突变的人类急性髓系白血病（AML）细胞中也观察到 SOCS2 下调。RAS 突变型 AML 细胞在 SOCS2 基因座处表现出增强子活性标记物 H3K27ac 的抑制。最后，在 RAS 突变型 AML 细胞中恢复 SOCS2 可减轻白血病的生长。因此，我们发现了一个新的信号反馈回路，其中高活性 Ras 信号通过抑制 Socs2 激活 Jak2/Stat5。
