β-catenin and γ-catenin are dispensable for T lymphocytes and AML leukemic stem cells

  1. Xin Zhao
  2. Peng Shao
  3. Kexin Gai
  4. Fengyin Li
  5. Qiang Shan
  6. Hai-Hui Xue  Is a corresponding author
  1. Hackensack University Medical Center, United States
  2. University of Iowa, United States

Abstract

The β-catenin transcriptional coregulator is involved in various biological and pathological processes; however, its requirements in hematopoietic cells remain controversial. We re-targeted the Ctnnb1 gene locus to generate a true β-catenin-null mutant mouse strain. Ablation of β-catenin alone, or in combination with its homologue γ-catenin, did not affect thymocyte maturation, survival or proliferation. Deficiency in β/γ-catenin did not detectably affect differentiation of CD4+ T follicular helper cells or that of effector and memory CD8+ cytotoxic cells in response to acute viral infection. In an MLL-AF9 AML mouse model, genetic deletion of β-catenin, or even all four Tcf/Lef family transcription factors that interact with β-catenin, did not affect AML onset in primary recipients, or the ability of leukemic stem cells (LSCs) in propagating AML in secondary recipients. Our data thus clarify on a long-standing controversy and indicate that β-catenin is dispensable for T cells and AML LSCs.

Data availability

Source data files provided. Mouse strain will be made available to other investigators upon publication of this work.

Article and author information

Author details

  1. Xin Zhao

    Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Peng Shao

    Microbiology and Immunology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kexin Gai

    Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Fengyin Li

    Microbiology and Immunology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiang Shan

    Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Hai-Hui Xue

    Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, United States
    For correspondence
    haihui.xue@hmh-cdi.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9163-7669

Funding

National Institute of Allergy and Infectious Diseases (AI121080)

  • Hai-Hui Xue

National Institute of Allergy and Infectious Diseases (AI139874)

  • Hai-Hui Xue

U.S. Department of Veterans Affairs (BX002903)

  • Hai-Hui Xue

National Institute of Allergy and Infectious Diseases (AI112579)

  • Hai-Hui Xue

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse experiments were performed under protocols approved by the Institutional Animal Use and Care Committees of the University of Iowa and the Hackensack University Medical Center(Protocol No. 8021178) and Center for Discovery and Innovation, Hackensack University Medical Center (Protocol No. 276.00).

Copyright

© 2020, Zhao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,636
    views
  • 239
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xin Zhao
  2. Peng Shao
  3. Kexin Gai
  4. Fengyin Li
  5. Qiang Shan
  6. Hai-Hui Xue
(2020)
β-catenin and γ-catenin are dispensable for T lymphocytes and AML leukemic stem cells
eLife 9:e55360.
https://doi.org/10.7554/eLife.55360

Share this article

https://doi.org/10.7554/eLife.55360

Further reading

    1. Immunology and Inflammation
    2. Neuroscience
    Sachin P Gadani, Saumitra Singh ... Pavan Bhargava
    Short Report

    While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Hoang Thanh Hai, Le Thanh Hoang Nhat ... Nguyen Thuy Thuong Thuong
    Research Article

    Mortality and morbidity from tuberculous meningitis (TBM) are common, primarily due to inflammatory response to Mycobacterium tuberculosis infection, yet the underlying mechanisms remain poorly understood. We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals. We employed multivariate elastic-net Cox regression to select candidate predictors of death, then logistic regression and internal bootstrap validation to choose best predictors. Increased neutrophil activation and decreased T and B cell activation pathways were associated with TBM mortality. Among HIV-positive individuals, mortality associated with increased angiogenesis, while HIV-negative individuals exhibited elevated TNF signaling and impaired extracellular matrix organization. Four hub genes—MCEMP1, NELL2, ZNF354C, and CD4—were strong TBM mortality predictors. These findings indicate that TBM induces a systemic inflammatory response similar to PTB, highlighting critical genes and pathways related to death, offering insights for potential therapeutic targets alongside a novel four-gene biomarker for predicting outcomes.