The Role of Histone Demethylase Jmjd3 in Immune-Mediated Aplastic Anemia
Abstract
Acquired aplastic anemia (AA) is a condition of bone marrow failure (BMF) characterized by blood pancytopenia and BM hypoplasia. In most cases, AA is an immune-mediated disorder with destruction of hematopoietic stem and progenitor cells by T cells. Immunosuppressive therapy with antithymocyte globulin in combination with cyclosporin A (CsA) can induce a hematologic response in about two-thirds of AA patients. However, relapse occurs in up to 35% of AA patients when CsA is withdrawn at 6 months. Allogeneic BM transplantation (BMT) has significantly improved the survival of AA. However, graft-versus-host disease (GVHD) remains a major barrier to the success of the procedure. Novel approaches are needed to improve the outcomes of AA treatment. Histone methylation plays critical roles in immune cell proliferation, survival, and function through orchestrating gene expression. For example, trimethylation of histone H3 at lysine 27 (referred to as H3K27me3) is associated with gene repression, whereas trimethylation of histone H3 at lysine 4 (referred to as H3K4me3) is associated with activation of gene expression. Histone methylation is catalyzed by methyltransferases that add methyl groups to histones, whereas histone demethylation is mediated by demethylases that remove methyl groups from histones. Jmjd3 is a histone demethylase essential for the initiation and maintenance of transcription programs by catalyzing demethylation of H3K27me3. Our central hypothesis is that (A) Jmjd3 is a new critical regulator of inflammatory T cell responses that mediate AA and (B) pharmacologic inhibition of Jmjd3 can reduce the proliferation, survival, and effector differentiation of bone marrow-destructing T cells. This hypothesis was formed based on our preliminary findings: (1) Jmjd3 was a downstream mediator of T cell receptor (TCR) signaling in T cells. Jmjd3 mRNA and protein were quickly upregulated in na?ve T cells as early as 4 hours in cultures following TCR activation, but declined by 24 hours after activation; (2) Jmjd3 was critical for the proliferation and expansion of TCR-activated T cells. Inhibiting Jmjd3 using GSK-J4, which is a selective inhibitor of H3K27me3 demethylases and has greater inhibitory effects on Jmjd3 than Utx, resulted in dramatically decreased proliferation of TCR-activated T cells. This was accompanied with increased H3K27me3, confirming the reduction of Jmjd3 activity; and (3) in vivo treatment with GSK-J4 improved survival of sublethally irradiated BDF1 mice (H-2b/d) receiving C57BL/6 mice (B6, H-2b), suggesting the attenuation of AA. This proposal is designed to test our hypothesis as the following. The first aim is designed to determine the roles of Jmjd3 in regulating the generation and maintenance of BM-destructive T cells in experimental mice. Understanding the cellular mechanism of Jmjd3 action in these cells is essential to establish why pharmacologic inhibition of Jmjd3 reduced BMF. The second aim is to define the molecular mechanisms by which Jmjd3 regulates the generation and maintenance of AA-mediating T cells. Specifically, we will examine how Jmjd3 and Ezh2 (which is a histone methyltransferase regulating T cell immune response) coordinately regulate T cell production of IFN-gamma induction of AA. Finally, we will assess the therapeutic effects of pharmacologic inhibition of Jmjd3 on AA in mice. Mouse models of BMF will be used to study the effect of pharmacologic inhibition of Jmjd3 on blockade of AA. We will examine whether inhibiting Jmjd3 prevents AA by administration of GSK-J4 and how hematopoiesis may be restored to normal levels following GSK-J4 treatment in mice. Our long-term goal is to develop a novel and clinically relevant approach to control inflammatory T cells causing BMF and GVHD. Our objective in this application is to identify the roles of Jmjd3 in marrow-destructing T cells, to define Jmjd3-regulated molecular mechanisms that regulate production and main
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1610055
Entities
People
- Yi Zhang
Organizations
- Temple University
- United States Army