SCL/TAL1 is a hematopoietic-specific transcription factor of the basic helix-loop-helix (bHLH) family that essential for erythropoiesis. Here we identify erythroid cell-specific glycophorin A gene (GPA) as target SCL in primary hematopoietic cells and show occupies GPA locus vivo. promoter activation dependent on assembly multifactorial complex containing well ubiquitous (E47, Sp1, Ldb1) tissue-specific (LMO2 GATA-1) factors. In addition, our observations suggest functional specialization...

Deciphering molecular events required for full transformation of normal cells into cancer remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding TAL1/SCL and LMO1/2 transcription factors are recurring targets chromosomal translocations, whereas NOTCH1 is activated in >50% samples. Here we show that SCL LMO1 oncogenes collaborate to expand primitive thymocyte progenitors inhibit later stages differentiation. Together with pre-T-cell antigen receptor...

The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model define the critical initiating events in this disease. First, thymocytes reprogrammed by SCL and LMO1 transcription factors pre-leukemic (pre-LSCs) remain non-malignant, evidenced their capacities generate functional T cells. Second, provide strong...

Neuroblastoma, a malignant neoplasm of the sympathetic nervous system, is one most aggressive pediatric cancers. Patients with stage IV high-risk neuroblastoma receive an intensive multimodal therapy ending immunotherapy based on chimeric monoclonal antibody ch14.18. Although use ch14.18 has significantly increased survival rate patients, about 33% these patients still relapse and die from their disease. Ch14.18 targets disialoganglioside, GD2, expressed neuroblastic tumor (NT) cells. To...

The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). encodes two products, E12 and E47, that are part the basic helix-loop-helix (bHLH) family transcription factors central B lineage differentiation. haplo-insufficiency hinders progression through three major checkpoints development: commitment into lineage, at pro-B to pre-B transition, induction immunoglobulin M (IgM) expression required for functional BCR. These observations...

Lymphoid differentiation and activation critically depend on cytokine stimulation the interleukin-7 (IL-7) signaling in particular. Although it has been demonstrated that IL-7 may play a role natural killer (NK) cell maturation, effect of mature human NK cells not studied. We, therefore, investigated expression functional activity IL-7Ralpha populations from adult blood. In this article, we demonstrate is specifically expressed CD56bright noncytotoxic cytokine-producing subset. Importantly,...

The expression of the pT alpha gene is required for effective selection, proliferation, and survival beta T-cell receptor (beta TCR)-expressing immature thymocytes. Here, we have identified two phylogenetically conserved E-boxes within enhancer sequence that are optimal activity its stage-specific in T cells. We shown transcription factors E2A HEB associate with high affinity to these E-boxes. Moreover, as a direct target E2A-HEB heterodimers thymocytes because they specifically occupy vivo....

Abstract T cell differentiation in the thymus is dependent upon signaling through TCR and characterized by resulting changes expression patterns of CD4 CD8 surface coreceptor molecules. Although recent studies have effects proximal on differentiation, downstream integration these signals remains largely unknown. The growth factor independence-1 (GFI1) GFI1B transcriptional repressors may regulate cytokine pathways to affect lymphocyte survival. In this study, we show that Gfi1 induced...

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent relapse following HSCT, we aim to improve early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on adoptive transfer Therapeutic Inducers Natural Killer Killing (ThINKK). ThINKK expanded and differentiated from HSC, exhibit blood plasmacytoid dendritic (pDC) features. We...

Acute lymphoblastic leukemia (ALL) is believed to be resistant NK cell-mediated killing. To overcome this resistance, we developed an innovative approach based on cell stimulation with Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC). The translation of into the clinic requires production high numbers human pDC. Herein, show that in vitro differentiation cord blood CD34+ progenitors presence aryl hydrocarbon antagonists gives rise clinically relevant pDC, as about 108...

// Martin Lelaidier 1,2 , Yildian Dìaz-Rodriguez Martine Cordeau Paulo Cordeiro 1 Elie Haddad 1,2,3,4 Sabine Herblot 1,3 and Michel Duval 1,3,4 Groupe de Recherche en Transplantation & Immunologie du Sang Cordon (GRETISC), Centre Cancérologie Charles-Bruneau, recherche CHU Sainte-Justine, Montréal, Québec, Canada 2 Département Microbiologie Infectiologie Immunologie, Université 3 Pédiatrie, 4 Sciences Biomédicales, Correspondence to: Herblot, email: Keywords : pediatric acute lymphoblastic...

High-risk neuroblastoma (NB) remains a major therapeutic challenge despite the recent advent of disialoganglioside (GD2)-antibody treatment combined with interleukin (IL)-2 and granulocyte monocyte-colony stimulating factor (GM-CSF). Indeed, more than one third patients still die from this disease. Here, we developed novel approach to improve current anti-GD2 immunotherapy based on NK cell stimulation using toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDCs). We...

Physiological modulation of the immune system is required for foetal tolerance during pregnancy. However, this regulation might lead to impaired self-defence against pathogens. Indeed, pregnant women are more susceptible newly encountered viruses comparing non-pregnant women, as exemplified by prevalence severe complications in infected with pandemic influenza virus 2009. Plasmacytoid dendritic cells (pDCs) specialized that recognise viral antigens and initiate both innate adaptive...

IL-2 induces growth, differentiation, and/or apoptosis of lymphoid cells. To study further the molecular basis function, we used a cDNA subtraction approach involving cell line grown in or IL-4. From corresponding library, 66 nonredundant sequences were characterized; 16 them encode identified proteins. The kinetics vitro expression 8 selected sequences, functions which could be associated with IL-2-induced T activation/differentiation, was investigated using an IL-2-dependent line....

Plasmacytoid dendritic cells (pDCs) initiate both innate and adaptive immune responses, making them attractive targets for post-transplantation immunotherapy, particularly after cord blood transplantation (CBT). Toll-like receptor (TLR) agonists are currently studied pDC stimulation in various clinical settings. Their efficacy depends on number functionality, which unknown CBT. We performed a longitudinal study of reconstitution children who underwent bone marrow (BMT) single-unit Both CBT...

In order to dissect the molecular mechanisms of monocytic differentiation we have developed a subtractive hybridisation method based on simplified `representational difference analysis'. We selected 16 sequences and confirmed their down‐regulation along TPA‐induced HL60 cells. Among these identified α‐tubulin, TaxREB protein two ribosomal which had not been previously described as differentially expressed. These results add our knowledge about molecules implicated growth arrest leukemic...

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors, together with NOTCH1 pre-T cell receptor (TCR) signalling. Importantly, perturbations of early regulatory networks are implicated in leukemogenesis. gain function mutations invariably lead to acute lymphoblastic leukemia (T-ALL), whereas inhibition proteins accelerates Thus, NOTCH1, pre-TCR, E2A HEB functions intertwined, but how these pathways...