Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation.

The multifunctional RNA-binding protein hnRNPL is implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, germinal center formation, and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis.

The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis.

Unlabelled: The X-linked gene DDX3X encodes an RNA helicase that is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis, causing early developmental arrest.

GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors.

Growth factor indepdendent 1 (GFI1) is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation through molecular mechanisms and co-factors that still remain to be clearly identified. Here we show that GFI1 associates with the chromodomain helicase DNA binding protein 4 (CHD4) and other components of the Nucleosome remodeling and deacetylase (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes regulated by active or bivalent promoters and enhancers.

Severe Inflammatory Reactions in Mice Expressing a GFI1 Mutant Defective in Binding to the Histone Demethylase KDM1A (LSD1).

GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and histone deacetylases (HDACs). To study the consequences of the disruption of the complex between GFI1 and histone-modifying enzymes, we have used knock-in mice harboring a P2A mutation in GFI1 coding region that renders it unable to bind LSD1 and associated histone-modifying enzymes such as HDACs. GFI1 mice die prematurely and show increased numbers of memory effector and regulatory T cells in the spleen accompanied by a severe systemic inflammation with high serum levels of IL-6, TNF-α, and IL-1β and overexpression of the gene encoding the cytokine oncostatin M (OSM).

The transcription factors GFI1 and GFI1B as modulators of the innate and acquired immune response.

GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal CH zinc finger motifs that are almost identical in sequence and bind to very similar, specific DNA sites. The second is an N-terminal 20 amino acid SNAG domain that can bind to the pocket of the histone demethylase KDM1A (LSD1) near its active site. When bound to DNA, both proteins act as bridging factors that bring LSD1 and associated proteins into the vicinity of methylated substrates, in particular histone H3 or TP53.

Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models.

Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer that mainly affects children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage lead to health problems later in life, underlining the need for improved therapies. MYC is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy.

A novel regulatory circuit between p53 and GFI1 controls induction of apoptosis in T cells.

Here we demonstrate a mode of reciprocal regulation between GFI1 and p53 that controls the induction of apoptosis in T cells. We show that GFI1 prevents induction of p53 dependent apoptosis by recruiting LSD1 to p53, which leads to the demethylation of its C-terminal domain. This is accompanied by a decrease of the acetylation of lysine 117 within the core domain of the murine p53 protein, which is required for transcriptional induction of apoptosis.

Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice.

Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating gene expression and limits the activation of p53 by facilitating its de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 in mice causes a fatal myeloproliferative disease (MPN) that could progress to leukemia after additional mutations.

GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1.

GFI1 is a transcriptional regulator expressed in lymphoid cells, and an "oncorequisite" factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins.

The role of the transcriptional repressor growth factor independent 1 in the formation of myeloid cells.

Purpose Of Review: Growth factor independent 1 (Gfi1) is a transcriptional repressor that plays multiple roles during myeloid commitment and development. Gfi1-deficient mice lack granulocytes, accumulate aberrant monocytes and show a hyperactivity of macrophages toward bacterial cell wall components. Since these initial findings, numerous additional studies have confirmed the role of Gfi1 in myeloid differentiation from hematopoietic stem cells and multipotent progenitors to bipotential lymphoid/myeloid precursors and myeloid effector cells.

Threshold Levels of Gfi1 Maintain E2A Activity for B Cell Commitment via Repression of Id1.

A regulatory circuit that controls myeloid versus B lymphoid cell fate in hematopoietic progenitors has been proposed, in which a network of the transcription factors Egr1/2, Nab, Gfi1 and PU.1 forms the core element. Here we show that a direct link between Gfi1, the transcription factor E2A and its inhibitor Id1 is a critical element of this regulatory circuit.

Heterogeneous Nuclear Ribonucleoprotein L is required for the survival and functional integrity of murine hematopoietic stem cells.

The proliferation and survival of hematopoietic stem cells (HSCs) has to be strictly coordinated to ensure the timely production of all blood cells. Here we report that the splice factor and RNA binding protein hnRNP L (heterogeneous nuclear ribonucleoprotein L) is required for hematopoiesis, since its genetic ablation in mice reduces almost all blood cell lineages and causes premature death of the animals. In agreement with this, we observed that hnRNP L deficient HSCs lack both the ability to self-renew and foster hematopoietic differentiation in transplanted hosts.

T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1.

T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions.

Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis.

Objective: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR).

Methods: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew.

Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis.

Objective: From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA.

Immunologic effects of rituximab on the human spleen in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell-related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated.

Cytotoxic dendritic cells generated from cancer patients.

Known for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models.

Dendritic cell-tumor cell hybrids and immunotherapy: what's next?

Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation still require optimization.

Peroxynitrite-dependent killing of cancer cells and presentation of released tumor antigens by activated dendritic cells.

Dendritic cells (DCs), essential for the initiation and regulation of adaptive immune responses, have been used as anticancer vaccines. DCs may also directly trigger tumor cell death. In the current study, we have investigated the tumoricidal and immunostimulatory activities of mouse bone marrow-derived DCs.

Signaling pathways induced by a tumor-derived vaccine in antigen presenting cells.

We have previously reported on the anti-tumoral potential of a chaperone-rich cell lysate (CRCL) vaccine. Immunization with CRCL generated from tumors elicits specific T and NK cell-dependent immune responses leading to protective immunity in numerous mouse tumor models. CRCL provides both a source of tumor antigens and danger signals leading to dendritic cell activation.

Killer dendritic cells and their potential for cancer immunotherapy.

Known for years as the principal messengers of the immune system, dendritic cells (DC) represent a heterogeneous population of antigen presenting cells critically located at the nexus between innate and adaptive immunity. DC play a central role in the initiation of tumor-specific immune responses as they are endowed with the unique ability to take up, process and present tumor antigens to naïve CD4(+) or CD8(+) effector T lymphocytes. By virtue of the cytokines they produce, DC also regulate the type, strength and duration of T cell immune responses.

Dendritic cells trigger tumor cell death by a nitric oxide-dependent mechanism.

Dendritic cells (DCs) are well known for their capacity to induce adaptive antitumor immune response through Ag presentation and tumor-specific T cell activation. Recent findings reveal that besides this role, DCs may display additional antitumor effects. In this study, we provide evidence that LPS- or IFN-gamma-activated rat bone marrow-derived dendritic cells (BMDCs) display killing properties against tumor cells.