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See detailOutcome and risk factor analysis of molecular subgroups in cytogenetically normal AML treated by allogeneic transplantation
SCHMID, Christoph; LABOPIN, Myriam; SOCIE, Gerard et al

in Blood (2015)

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after ... [more ▼]

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) is limited. Therefore, we performed a retrospective registry analysis on 702 adults with CNAML undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1mut) and FLT3 internal tandem duplications (FLT3-ITD). Double negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. 2y-OS from HSCT was 81±5% in NPM1mut/FLT3wt (n=68), 75±3% in NPM1wt/FLT3wt (n=290), 66±3% in NPM1mut/FLT3-ITD (n=269) and 54±7% in NPM1wt/FLT3-ITD (n=75; p=0.003). Analysis of CEBPα among patients with NPM1wt/FLT3wt revealed excellent results both in patients with CEBPα mut (n=13, 2y-OS:100%), and with a triple negative genotype (n=138, 2y-OS:77±3%). In a Cox-model of predefined factors, older age, presence of FLT3-ITD and >1 course of chemotherapy to reach CR were associated with inferior outcome. 2y-OS/LFS were 88±3%/79±4% in patients without any, 77±2%/73±3% with one, and 53±4%/50±4 with>=2 risk factors (p=0.002 for LFS, p=0.003 for OS). Hence, FLT3-ITD proofed to be the decisive molecular marker for outcome after HSCT for CN-AML in CR1, regardless of NPM1 mutational status, variations of transplant protocols, or development of GvHD. Age, FLT3-ITD and response to induction chemotherapy allow for a prognostic risk classification. [less ▲]

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See detailFlow Cytometry Assessment of CD34+ Viability in Thawed Cord Blood Units: A Multi-Center Eurocord and Netcord Study
SACCARDI, RICCARDO; AZQUETA, Carmen; BALLERINI, Lara et al

in Blood (2014), 124

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See detailRIC allo-SCT with Flu/Bu in comparaison to Flu/Mel for AML results in similar overall survival: a report from the ALWP of the EBMT
BARON, Frédéric ULg; LABOPIN, Myriam; PENIKET, Andrew et al

in Blood (2014, December), 124(21), 545

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See detailP2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice
Darbousset, Roxane; Delierneux, Céline ULg; Mezouar, Soraya et al

in Blood (2014), 124

Adenosine Triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophils (PMNs) functions. PMNs have recently been implicated in the initiation of thrombosis. We ... [more ▼]

Adenosine Triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophils (PMNs) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449 a P2X1 antagonist. Infusion of wild-type PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from wild-type mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that ATP contributes to PMN activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanisms by which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs. [less ▲]

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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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