Evidence map›Paper›PMID 35352806›Full record

ArticleDisease models & mechanisms2022

Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.

Xi Jin, Victor Ng, Meiling Zhao, Lu Liu, Tomoyasu Higashimoto, Zheng Hong Lee, Jooho Chung, Victor Chen, Gina Ney, Malathi Kandarpa and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Disease models & mechanisms, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
1.3field-weighted citation impact, top 19% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 8 citations in OpenAlex.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 1 institution in 1 country.

Xi JinDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.ORCID 0000-0003-0741-8736
Victor NgDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.ORCID 0000-0002-7428-0688
Meiling ZhaoDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Lu LiuDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Tomoyasu HigashimotoDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.ORCID 0000-0003-0435-065X
Zheng Hong LeeDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Jooho ChungDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Victor ChenDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Gina NeyDepartment of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Malathi KandarpaDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Moshe TalpazDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Qing LiDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.ORCID 0000-0002-4982-1024
University of Michigan · US

Funding

Postdoctoral Medical Genetics Training GrantT32GM007471 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI TAO WANG · 1985 to 2026
$8.0M
The role of ER associated degradation (ERAD) in hematopoietic stem cellsR01HL150707 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LI, QING · 2020 to 2024
$2.4M
Oncogenic Nras signaling in leukemic stem cell transformationR01HL132392 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LI, QING · 2016 to 2020
$1.9M
NHLBI NIH HHS R01 HL132392NHLBI NIH HHS R01 HL150707NIGMS NIH HHS T32 GM007471
6 · The paper itself

Abstract

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.

Indexed as

Epigenesis, GeneticGenes, rasHematologic NeoplasmsLeukemia, Myeloid, AcuteSuppressor of Cytokine Signaling ProteinsAnimalsDown-RegulationMiceSTAT5 Transcription FactorSocs2 protein, mouseSTAT5 Transcription FactorSuppressor of Cytokine Signaling ProteinsEpigenetic regulationHematopoietic stem cellsJak/Stat signalingLeukemiaRAS signalingSOCS proteins

Identifiers

PMID35352806
PMCPMC9092650
OpenAlexW4221119818

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.