To our knowledge, we provide first proof of concept that natalizumab diminishes migratory capacity of immune cells. Our prospective study further shows that effects of therapy likely (1) differ for distinct immune cell subsets, (2) are not sustained over current dose interval, (3) have unique profiles in individual patients, and (4) include modulation of activation threshold of immune cells. Monitoring these parameters could be relevant to ongoing safety and efficacy considerations.
The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-offunction model. We conclude that Asxl1 is needed for normal hematopoiesis. IntroductionProteins of the Polycomb group (PcG) and trithorax group (trxG) ensure epigenetic maintenance of gene expression patterns through mitosis and faithful propagation of cell fates. PcG genes silence their targets, whereas trxG proteins maintain transcriptional activation. Although the precise mechanism of maintenance is unknown, trxG and PcG genes encode chromatin proteins required for histone modification or establishment or prevention of nucleosome remodeling, or those that enhance or prevent transcriptional elongation. 1 The Enhancer of trithorax and Polycomb (ETP) genes encode proteins required for both maintenance of activation and silencing, as shown by simultaneous anterior and posterior transformations caused by failure to activate or repress Hox genes. The molecular basis of ETP function is unknown. 2 Hematopoiesis is a dynamic process requiring coordination between genetic and epigenetic programs to regulate transitions between and maintenance of cell fates, which ultimately generates all blood lineages. Mammalian PcG and trxG genes display hematopoietic lineage-and differentiation stage-specific expression patterns, are required for normal and leukemic hematopoiesis, and show aberrant expression in leukemias and lymphomas. [3][4][5] Mutations in vertebrate PcG and trxG genes can lead to oncogenic or tumor suppressor activity, depending on context. [3][4][5] Additional sex combs like 1 (Asxl1) belongs to the ETP group. Asxl1 regulates Hox genes in axial patterning, 6 and is 1 of 3 mammalian homologs of the Drosophila Asx gene. 4,5,[7][8][9] As shown in Figure 1A, all mammalian ASXL proteins have conserved sequence features: an amino-terminal ASX homology (ASXH) region, which contains 2 putative nuclear receptor coregulator binding (NR box) motifs, 3 other NR box motifs, and a carboxyterminal plant homeodomain (PHD) domain. 7,8 ASXL1 is a member of a repressive complex containing histone H1.2. 9 Conversely, ASXL1 functio...
To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding fulllength human myelin basic protein, in patients with multiple sclerosis (MS). Design:The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding.Setting: The trial was conducted at 4 academic institutions within North America.Patients: Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years.Interventions: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). Main Outcome Measures:The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses.Results: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-␥-producing, myelinreactive CD4ϩ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. Conclusion:In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.
MEIS proteins form heteromeric DNA-binding complexes with PBX monomers and PBX⅐HOX heterodimers. We have shown previously that transcriptional activation by PBX⅐HOX is augmented by either protein kinase A (PKA) or the histone deacetylase inhibitor trichostatin A (TSA). To examine the contribution of MEIS proteins to this response, we used the chromatin immunoprecipitation assay to show that MEIS1 in addition to PBX1, HOXA1, and HOXB1 was recruited to a known PBX⅐HOX target, the Hoxb1 autoregulatory element following Hoxb1 transcriptional activation in P19 cells. Subsequent to TSA treatment, MEIS1 recruitment lagged behind that of HOX and PBX partners. MEIS1A also enhanced the transcriptional activation of a reporter construct bearing the Hoxb1 autoregulatory element after treatment with TSA. The MEIS1 homeodomain and protein-protein interaction with PBX contributed to this activity. We further mapped TSAresponsive and CREB-binding protein-dependent PKAresponsive transactivation domains to the MEIS1A and MEIS1B C termini. Fine mutation of the 56-residue MEIS1A C terminus revealed four discrete regions required for transcriptional activation function. All of the mutations impairing the response to TSA likewise reduced activation by PKA, implying a common mechanistic basis. C-terminal deletion of MEIS1 impaired transactivation without disrupting DNA binding or complex formation with HOX and PBX. Despite sequence similarity to MEIS and a shared ability to form heteromeric complexes with PBX and HOX partners, the PREP1 C terminus does not respond to TSA or PKA. Thus, MEIS C termini possess transcriptional regulatory domains that respond to cell signaling and confer functional differences between MEIS and PREP proteins. Meis11 (myeloid ecotropic viral insertion site 1) was identified at one of the common viral integration sites in myeloid leukemic cells of BXH-2 mice (1) and has been shown to promote oncogenic transformation in several contexts (2, 3). Meis1 and its fly homolog homothorax (hth) encode homeoproteins of the three-amino acid loop extension class and therefore are related to the vertebrate pre-B cell transformation (Pbx) genes and their fly homolog extradenticle (exd) (4, 5). Three genes constitute the mammalian Meis family (6 -10) with Meis1 transcripts alternatively spliced to yield multiple isoforms (1, 11). In addition, the Meis-related genes Prep1 and Prep2 (for PBX regulatory protein) have also been identified (12)(13)(14).MEIS/PREP/HTH proteins form stable heterodimers with PBX/EXD partners. In addition, PBX or MEIS family members bind DNA cooperatively with subsets of HOX partners (Ref. 15 and references therein), thus permitting the formation of DNAbound heterotrimeric MEIS⅐PBX⅐HOX complexes. These heterodimeric and trimeric complexes modulate the functional specificity of HOX proteins, perhaps by increasing DNA binding affinity and selectivity (16 -20) and/or by modulating coregulator interactions (21). PBX/EXD and MEIS/PREP/HTH are mutually dependent for accumulation in the nucleus (22-24), ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.