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See detailErythropoietin therapy after allogeneic hematopoietic cell transplantation : a prospective randomized trial
JASPERS, Aurélie ULg; Baron, Frédéric ULg; WILLEMS, Evelyne ULg et al

in Blood (2014), 124

We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (n=131) were ... [more ▼]

We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (n=131) were randomized (1:1) between no treatment (control arm) or erythropoietin (Neorecormon®) at 500 U/kg/week (EPO arm). Patients were also stratified in 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day 28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on day 28, and patients also given NMHCT but with rhEPO to start on day 0. The proportion of complete correctors (i.e. achieving Hb ≥ 13 g/dL) before day 126 post-transplant (primary endpoint) was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median time 90 days) (p<0.001). Hb levels were higher and transfusions requirements decreased (p<0.001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on day 0. There was no difference in rates of thrombo-embolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT. [less ▲]

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See detailNovel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia.
Shochat, Chen; Tal, Noa; Gryshkova, Vitalina et al

in Blood (2014), 124(1), 106-10

Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor alpha (IL7R) or cytokine receptor-like factor 2 (CRLF2 ... [more ▼]

Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor alpha (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand-independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations. [less ▲]

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See detailSurvival improvement of secondary acute myeloid leukemia over time: experience from 962 patients included in 13 EORTC-Gimema-HOVON leukemia group trials
RAMADAN, Safaa M.; SUCIU, Stefan; STEVENS-KROEF, Marian J.P.L. et al

in Blood (2013, November), 122(21), 829

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See detailMatrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.
Detry, Benoît ULg; Erpicum, Charlotte ULg; Paupert, Jenny ULg et al

in Blood (2012), 119(21), 5048-56

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to ... [more ▼]

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density and cross-linking). Transmission electron microscopy (TEM) and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LEC associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LEC negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis. [less ▲]

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See detailInteraction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program
Boxus, Mathieu ULg; Twizere, Jean-Claude ULg; Legros, Sébastien et al

in Blood (2012), 119

The Tax oncoprotein encoded by the Human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in viral persistence and pathogenesis. HTLV-1 infected cells proliferate faster than normal lymphocytes ... [more ▼]

The Tax oncoprotein encoded by the Human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in viral persistence and pathogenesis. HTLV-1 infected cells proliferate faster than normal lymphocytes, expand through mitotic division and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax modulates the spatiotemporal program of origin activation and fires supplementary origins at the onset of S phase. Thereby, Tax increases the DNA replication rate, accelerates S phase progression but also generates a replicative stress characterized by the presence of genomic lesions. Mechanistically, Tax favors p300 recruitment and histone hyperacetylation at late replication domains advancing their replication timing in early S phase. [less ▲]

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See detailSafety of long-term treatment of HAM/TSP patients with valproic acid
Olindo, Stéphane; Belrose, Gildas; Gillet, Nicolas ULg et al

in Blood (2011), 118(24), 6306-6309

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential ... [more ▼]

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential therapeutic approach, we previously suggested reducing the proviral load (PVL) by modulating lysine deacetylase activity using valproic acid (VPA) and exposing virus-positive cells to the host immune response. We conducted a single-center, two-year open-label trial, with 19 HAM/TSP volunteers treated with oral VPA. PVL, CD38/HLA-DR expression and CD8+ lysis efficiency were not significantly affected by VPA. Mean scores of HAM/TSP disability did not differ between baseline and final visit. Walking Time Test (WTT) increased significantly (>20%) in 3 patients and was in keeping with minor VPA side effects (drowsiness and tremor). WTT improved rapidly after VPA discontinuation. We conclude that long term treatment with VPA is safe in HAM/TSP. [less ▲]

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See detailOpposite effects of valproate on Tax and HBZ expressions in T-lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients.
Belrose, Gildas; Gross, Antoine; Olindo, Stéphane et al

in Blood (2011), 118(9), 2483-2491

A determinant of human T-lymphotropic virus-1 (HTLV-1)–associated myelopathy/ tropical spastic paraparesis (HAM/TSP) development is the HTLV-1–infected cell burden. Viral proteins Tax and HBZ, encoded by ... [more ▼]

A determinant of human T-lymphotropic virus-1 (HTLV-1)–associated myelopathy/ tropical spastic paraparesis (HAM/TSP) development is the HTLV-1–infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of th pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4 - cel clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of proviruspositive CD4 T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax positive–infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and GagmRNA levels peaked spontaneously, before declining concomitantly to HBZmRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome ofVPAtreatment on HTLV-1–infected– cell proliferation and survival. [less ▲]

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See detailThe host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones.
Gillet, Nicolas ULg; Malani, Nirav; Melamed, Anat et al

in Blood (2011), 117(11), 3113-22

Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1-infected clones remain unknown. We devised a high-throughput protocol to map the genomic location and quantify the abundance of > 91,000 unique insertion sites of the provirus from 61 HTLV-1(+) persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1-infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1-associated inflammatory disease results from a larger number of unique insertion sites than in asymptomatic carriers and not, as previously thought, from a difference in clonality. The abundance of established HTLV-1 clones is determined by genomic features of the host DNA flanking the provirus. HTLV-1 clonal expansion in vivo is favored by orientation of the provirus in the same sense as the nearest host gene. [less ▲]

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See detailDentin Matrix Protein 1 induces membrane expression of VE-cadherin on endothelial cells and inhibits VEGF-induced angiogenesis by blocking VEGFR-2 phosphorylation.
Pirotte, Sophie ULg; Lamour, Virginie ULg; Lambert, Vincent ULg et al

in Blood (2011), 117(8), 2515-26

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices ... [more ▼]

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although pro-angiogenic activities have been demonstrated for two SIBLINGs, the role of DMP1 in angiogenesis has not been addressed yet. We demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate VEGFR-2 activity, the major high affinity receptor for VEGF. DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner. VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC. Indeed, subsequently to VE-cadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with bFGF-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis. [less ▲]

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See detailImpact of chronic graft-versus-host disease (GVHD) after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) as treatment for acute myeloid leukemia (AML) : a survey from the Acute Leukemia Working Party of the EBMT
Baron, Frédéric ULg; Labopin, Myriam; Niederwieser, Dietger et al

in Blood (2011), 118

The goal of RIC allo-SCT is to harness the graft-versus-leukemia (GVL) effect, while minimizing toxicities and the risk of GVHD. However, prior studies have shown a lower risk of relapse in AML patients ... [more ▼]

The goal of RIC allo-SCT is to harness the graft-versus-leukemia (GVL) effect, while minimizing toxicities and the risk of GVHD. However, prior studies have shown a lower risk of relapse in AML patients (pts) who experienced chronic GVHD after RIC allo-SCT versus in those who did not. Here, we investigated the impact of occurrence of GVHD on transplantation outcomes in a large cohort of AML pts given allogeneic PBSC after RIC conditioning. Data from 1859 AML pts in first (n=1439) or second (n=420) CR transplanted between 2000 and 2009 following a RIC regimen at EBMT affiliated centres were analyzed. Pts were given PBSC from HLA-identical sibling (MRD, n=1208), or from HLA-matched unrelated donors (MUD, n=651). Median pt age at transplantation was 56 y (range, 18–77). 338 male pts were given grafts from female donors. RIC was based on low-dose TBI in 520 (28%) pts, while the remaining pts received chemotherapy-based RIC. ATG was given in 269 (22%) MRD and in 267 (41%) MUD recipients, respectively, while 151 (13%) MRD and 165 (25%) MUD recipients received in-vivo T cell depletion with alemtuzumab. The impact of chronic GVHD on relapse risk, non-relapse mortality (NRM), leukemia-free survival (LFS), and overall survival (OS) was assessed using time-dependent multivariate Cox models and in a landmark analysis at 18 months after transplant. Three-year incidences of relapse, NRM, LFS and OS were 34±1%, 15±1%, 51±2% and 60±2% in MRD recipients, respectively, and 34±2% (p=NS), 24±2% (P<0.001), 42±2% (P=0.001) and 47±2% (P=0.001) in MUD recipients, respectively. Grade II, III and IV acute GVHD were observed in 133 (11%), 61 (5%) and 30 (2%) MRD recipients and in 119 (18%), 41 (6%) and 24 (4%) MUD recipients, respectively. The 3-y cumulative incidence of chronic GVHD was 47%. Fifty-three percent of patients with chronic GVHD had extensive chronic GVHD, while the remaining 47% had limited chronic GVHD. In multivariate analyses, occurrence of grade II-IV acute GVHD was associated with a lower risk of relapse (HR=0.8; P=0.04), a higher risk of chronic (HR=2.2; P<0.001) and extensive chronic GVHD (HR=2.8; P<0.001), a higher risk of NRM (HR=2.4 P<0.001), a worsened LFS (HR=1.3; P=0.01), and a worsened OS (HR=1.5; P<0.001). In multivariate time-dependent analyses, occurrence of limited chronic GVHD was associated with a lower risk of relapse (HR=0.7; P=0.05), comparable NRM (HR=1.4; P=0.16), comparable LFS (HR=0.9; P=0.29) and better OS (HR=0.5; P<0.001), while occurrence of extensive chronic GVHD was associated with a lower risk of relapse (HR=0.6; P=0.01), higher NRM (HR=3.2; P<0.001), a trend for worsened LFS (HR=1.3; P=0.06) and comparable OS (HR=0.9; P=0.34). The median interval from transplantation to occurrence of chronic GVHD was 163 (range, 100–1545) days. To further assess the graft-versus-leukemia effect of chronic GVHD, we performed a landmark analysis in patients who were leukemia-free at 18 months after transplantation (n=776). Median follow-up from this landmark time-point was 24 (range, 0.1–112) months. Two-year relapse, NRM, LFS and OS were 16±2%, 2.5±1%, 82±2%, and 89±2%, respectively, in patients without chronic GVHD before the landmark time-point, versus 9±1% (P=0.001), 8±1% (P<0.001), 83±2% (P=0.65), and 86±2% (P=0.38), respectively, in patients with chronic GVHD before the landmark time-point.In conclusion, in this cohort of AML patients transplanted in remission, occurrence of chronic GVHD was associated with a lower risk of relapse that translated to better OS in patients with limited chronic GVHD but not in those with extensive chronic GVHD who experienced higher long term NRM, highlighting the need for long term prospective assessment of long term effects and quality of life in patients receiving RIC allo-SCT. [less ▲]

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See detailB cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia
Kerns, H. M.; Ryu, B. Y.; Stirling, B. V. et al

in Blood (2010), 115(11), 2146-55

The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell ... [more ▼]

The immunodeficiency disorder, X-linked agammaglobulinemia (XLA), results from mutations in the gene encoding Bruton tyrosine kinase (Btk). Btk is required for pre-B cell clonal expansion and B-cell antigen receptor signaling. XLA patients lack mature B cells and immunoglobulin and experience recurrent bacterial infections only partially mitigated by life-long antibody replacement therapy. In pursuit of definitive therapy for XLA, we tested ex vivo gene therapy using a lentiviral vector (LV) containing the immunoglobulin enhancer (Eµ) and IgB (B29) minimal promoter to drive B lineage-specific human Btk expression in Btk/Teck-/- mice, a strain that reproduces the features of human XLA. After transplantation of EµB29-Btk-LV-transduced stem cells, treated mice showed significant, albeit incomplete, rescue of mature B cells in the bone marrow, peripheral blood, spleen, and peritoneal cavity, and improved responses to T-independent and T-dependent antigens. LV-teated B cells exhibited enhanced B-cell antigen receptor signaling and an in vivo selective advantage in the peripheral versus central B-cell compartment. Secondary transplantation showed sustained Btk expression, viral integration, and partial functional responses, consistent with long-term stem cell marking; and serial transplantation revealed no evidence for cellular or systemic toxicity. These findings strongly support pursuit of B lineage-targeted LV gene therapy in human XLA. [less ▲]

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See detailInterleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities
Eddahri, Fouad; Denanglaire, Sebastien; Bureau, Fabrice ULg et al

in Blood (2009), 113(11), 2426-2433

The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6 ... [more ▼]

The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6-driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell-specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (T(FH)) differentiation [less ▲]

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See detailAngiostatic activity of the antitumor cytokine interleukin-21.
Castermans, Karolien ULg; Tabruyn, Sébastien ULg; Zeng, Rong et al

in Blood (2008), 112(13), 4940-7

Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ... [more ▼]

Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis. [less ▲]

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See detailCyclin D1-negative mantle cell lymphoma with cryptic t(12;14)(p13;q32) and cyclin D2 overexpression.
Herens, Christian ULg; Lambert, Frédéric ULg; Quintanilla-Martinez, Leticia et al

in Blood (2008), 111(3), 1745-6

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