Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation
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 mec...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-05-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/15/5/dmm049088 |
| _version_ | 1811257867306532864 |
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| author | Xi Jin Victor Ng Meiling Zhao Lu Liu Tomoyasu Higashimoto Zheng Hong Lee Jooho Chung Victor Chen Gina Ney Malathi Kandarpa Moshe Talpaz Qing Li |
| author_facet | Xi Jin Victor Ng Meiling Zhao Lu Liu Tomoyasu Higashimoto Zheng Hong Lee Jooho Chung Victor Chen Gina Ney Malathi Kandarpa Moshe Talpaz Qing Li |
| author_sort | Xi Jin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T18:04:16Z |
| format | Article |
| id | doaj.art-59507399254546bcbfb824add9ce3b5b |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T18:04:16Z |
| publishDate | 2022-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-59507399254546bcbfb824add9ce3b5b2022-12-22T03:22:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-05-0115510.1242/dmm.049088049088Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulationXi Jin0Victor Ng1Meiling Zhao2Lu Liu3Tomoyasu Higashimoto4Zheng Hong Lee5Jooho Chung6Victor Chen7Gina Ney8Malathi Kandarpa9Moshe Talpaz10Qing Li11 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA 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.http://dmm.biologists.org/content/15/5/dmm049088ras signalingjak/stat signalingsocs proteinshematopoietic stem cellsleukemiaepigenetic regulation |
| spellingShingle | Xi Jin Victor Ng Meiling Zhao Lu Liu Tomoyasu Higashimoto Zheng Hong Lee Jooho Chung Victor Chen Gina Ney Malathi Kandarpa Moshe Talpaz Qing Li Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation Disease Models & Mechanisms ras signaling jak/stat signaling socs proteins hematopoietic stem cells leukemia epigenetic regulation |
| title | Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation |
| title_full | Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation |
| title_fullStr | Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation |
| title_full_unstemmed | Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation |
| title_short | Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation |
| title_sort | epigenetic downregulation of socs2 contributes to mutant n ras mediated hematopoietic dysregulation |
| topic | ras signaling jak/stat signaling socs proteins hematopoietic stem cells leukemia epigenetic regulation |
| url | http://dmm.biologists.org/content/15/5/dmm049088 |
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