Retraction: EPO Receptor Gain-of-Function Causes Hereditary Polycythemia, Alters CD34+ Cell Differentiation and Increases Circulating Endothelial Precursors

Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.

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Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling

Blood ◽

10.1182/blood-2012-10-463158 ◽

2013 ◽

Vol 122 (2) ◽

pp. 262-271 ◽

Cited By ~ 16

Author(s):

Neli S. Slavova-Azmanova ◽

Nicole Kucera ◽

Jiulia Satiaputra ◽

Leah Stone ◽

Aaron Magno ◽

...

Keyword(s):

Red Blood Cells ◽

Hemolytic Anemia ◽

Blood Cells ◽

Receptor Signaling ◽

Gain Of Function ◽

Epo Receptor ◽

Key Points ◽

Extramedullary Erythropoiesis

Key Points Gain-of-function Lyn mice develop hemolytic anemia with acanthocyte red blood cells and display compensatory extramedullary erythropoiesis. Hyperactive Lyn notably alters Epo receptor signaling, particularly an Akt-FoxO3 pathway, enhancing viability and delaying differentiation.

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Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02402-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sung-Tai Wei ◽

Yen-Chih Huang ◽

Jung-Ying Chiang ◽

Chia-Ching Lin ◽

Yu-Jung Lin ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Tissue Regeneration ◽

Chondrogenic Differentiation ◽

Human Mscs ◽

Gain Of Function ◽

Soluble Factors ◽

Therapeutic Benefits ◽

Anti Inflammatory

Abstract Background The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC-mediated osteogenic or chondrogenic differentiation and immunomodulation are unclear. Methods Gain of CXCR7 function on human MSCs was carried out by lentiviral vector-mediated CXCR7 overexpression or CXCR7 agonist, TC14012. These cells were determined the role and potential mechanisms for CXCR7-regulated MSC differentiation and immunomodulation using cellular and molecular assays. The therapeutic benefits in RA were investigated in rats with collagen-induced arthritis (CIA). Results CXCR7 was upregulated in MSCs during the induction of osteogenic or chondrogenic differentiation. Blockage of CXCR7 function inhibited osteogenic or chondrogenic differentiation of MSCs whereas gain of CXCR7 function had the opposite effects. Besides, MSCs with CXCR7 gain-of-function facilitated macrophage apoptosis and regulatory T cell differentiation in a co-culture system. Gain of CXCR7 function also promoted the production of anti-inflammatory soluble factors. A gene expression profiling assay and signaling reporter assays revealed that CXCR7 could regulate several candidate genes related to the PPAR, WNT, Hedgehog or Notch pathways, and their signaling activities, which are known to control cell differentiation and immunomodulation. Finally, MSCs with CXCR7 gain-of-function significantly reduced the articular index scores, ankle circumference, radiographic scores, histologic scores, and inflammation in rats with CIA compared with control MSCs. Conclusions CXCR7 promotes the osteogenic and chondrogenic differentiation of MSCs and MSC-mediated immunomodulation by regulating several signaling pathways and anti-inflammatory soluble factors. MSCs with CXCR7 gain-of-function significantly ameliorate arthritic symptoms in a CIA model.

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Impaired B-Cell Differentiation in a Patient With STAT1 Gain-of-Function Mutation

Frontiers in Immunology ◽

10.3389/fimmu.2020.557521 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kazuki Nemoto ◽

Toshinori Kawanami ◽

Takayuki Hoshina ◽

Masataka Ishimura ◽

Kei Yamasaki ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

B Cell Differentiation ◽

Gain Of Function

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Genetic Modifier Screens on Hairless Gain-of-Function Phenotypes Reveal Genes Involved in Cell Differentiation, Cell Growth and Apoptosis in Drosophila melanogaster

Genetics ◽

10.1534/genetics.105.044453 ◽

2005 ◽

Vol 171 (3) ◽

pp. 1137-1152 ◽

Cited By ~ 29

Author(s):

Dominik Müller ◽

Sabrina J. Kugler ◽

Anette Preiss ◽

Dieter Maier ◽

Anja C. Nagel

Keyword(s):

Drosophila Melanogaster ◽

Cell Differentiation ◽

Cell Growth ◽

Genetic Modifier ◽

Gain Of Function

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Loss- and gain-of-function mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation

Seminars in Immunology ◽

10.1006/smim.1998.0115 ◽

1998 ◽

Vol 10 (2) ◽

pp. 133-142 ◽

Cited By ~ 51

Author(s):

Aline M. Morrison ◽

Stephen L. Nutt ◽

Claire Thévenin ◽

Antonius Rolink ◽

Meinrad Busslinger

Keyword(s):

Cell Differentiation ◽

B Cell ◽

B Cell Differentiation ◽

Gain Of Function

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Electron microscope study of the secretory activity of epithelial cells in embryonic thymus

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010015945x ◽

1990 ◽

Vol 48 (3) ◽

pp. 382-383

Author(s):

H. Alasam

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Epithelial Cells ◽

Electron Density ◽

Secretory Activity ◽

T Cell Differentiation ◽

High Electron ◽

Transmission Electron ◽

Medullary Epithelial Cells ◽

Thymic Factor

The possibility that intrathymic T-cell differentiation involves stem cell-lymphoid interactions in embryos led us to study the ultrastructure of epithelial cell in normal embryonic thymus. Studies in adult thymus showed that it produces several peptides that induce T-cell differentiation. Several of them have been chemically characterized, such as thymosin α 1, thymopoietin, thymic humoral factor or the serum thymic factor. It was suggested that most of these factors are secreted by populations of A and B-epithelial cells.Embryonic materials were obtained from inbred matings of Swiss Albino mice. Thymuses were disected from embryos 17 days old and prepared for transmission electron microscopy. Our studies showed that embryonic thymus at this stage contains undifferentiated and differentiated epithelial cells, large lymphoblasts, medium and few small lymphocytes (Fig. 5). No differences were found between cortical and medullary epithelial cells, in contrast to the findings of Van Vliet et al,. Epithelial cells were mostly of the A-type with low electron density in both cytoplasm and nucleus. However few B-type with high electron density were also found (Fig. 7).

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