Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program
Boxus, Mathieu ; Twizere, Jean-Claude ; 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 ▲]Detailed reference viewed: 28 (9 ULg)
Safety of long-term treatment of HAM/TSP patients with valproic acid
; ; Gillet, Nicolas 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 ▲]Detailed reference viewed: 31 (8 ULg)
Opposite effects of valproate on Tax and HBZ expressions in T-lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients.
; ; 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 ▲]Detailed reference viewed: 21 (1 ULg)
The host genomic environment of the provirus determines the abundance of HTLV-1-infected T-cell clones.
Gillet, Nicolas ; ; 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 ▲]Detailed reference viewed: 11 (6 ULg)
Dentin Matrix Protein 1 induces membrane expression of VE-cadherin on endothelial cells and inhibits VEGF-induced angiogenesis by blocking VEGFR-2 phosphorylation.
Pirotte, Sophie ; Lamour, Virginie ; Lambert, Vincent 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 ▲]Detailed reference viewed: 189 (43 ULg)
Impact 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 ; ; 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 ▲]Detailed reference viewed: 72 (2 ULg)
B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia
; ; 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 ▲]Detailed reference viewed: 34 (1 ULg)
Thymic Recovery After Allogeneic Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning Might Be Limited to Patients Younger Than 60 Years of Age.
; Hannon, Muriel ; et al
in Blood (2009), 114(22), 1149Detailed reference viewed: 14 (5 ULg)
Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities
; ; Bureau, Fabrice 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 ▲]Detailed reference viewed: 62 (7 ULg)
Angiostatic activity of the antitumor cytokine interleukin-21.
Castermans, Karolien ; Tabruyn, Sébastien ; 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 ▲]Detailed reference viewed: 22 (1 ULg)
Cyclin D1-negative mantle cell lymphoma with cryptic t(12;14)(p13;q32) and cyclin D2 overexpression.
Herens, Christian ; Lambert, Frédéric ; et al
in Blood (2008), 111(3), 1745-6Detailed reference viewed: 60 (5 ULg)
Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis
; ; Humblet, Stéphanie et al
in Blood (2008), 112(10), 4158-69
To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central ... [more ▼]
To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro funtcional assays, we show that these dificits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that : (1) WASp expression levels increase with cell maturaity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease. [less ▲]Detailed reference viewed: 5 (0 ULg)
The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (T-FH) cells
de Leval, Laurence ; ; Thielen, Caroline et al
in Blood (2007), 109(11), 4952-4963
The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ... [more ▼]
The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell- and follicular dendritic cell-related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (T-FH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published T-FH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several T-FH genes was validated by immunohistochemistry in AITLs. A few cases with molecular T-FH-like features were identified among CD30(-) PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30(-) PTCLs-u may derive from or be related to AITL. [less ▲]Detailed reference viewed: 47 (10 ULg)
Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
; ; et al
in Blood (2007), 109(5), 1834-1840
Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly ... [more ▼]
Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with nonneoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis. [less ▲]Detailed reference viewed: 54 (3 ULg)
Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.
; Gillet, Nicolas ; et al
in Blood (2007), 110(10), 3722-8
Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated ... [more ▼]
Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. [less ▲]Detailed reference viewed: 43 (19 ULg)
Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling.
Twizere, Jean-Claude ; ; Boxus, Mathieu et al
in Blood (2007), 109(3), 1051-60
Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene ... [more ▼]
Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide-binding proteins (G proteins) and G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein beta subunit. Interestingly, though the G-protein beta subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein beta subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1-expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies. [less ▲]Detailed reference viewed: 261 (40 ULg)
Diffuse Large B-cell Lymphomas of the waldeyer's ring frequently have a germinal center-like phenotype: a clinico-pathological study of 209 patients from the groupe d'étude des lymphomes de l'adulte (GELA).
; Bonnet, Christophe ; et al
in Blood (2007)Detailed reference viewed: 10 (0 ULg)
What is the role for donor NK cells after nonmyeloablative conditioning ?
Baron, Frédéric ; ; et al
in Blood (2007), 110
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of ... [more ▼]
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of donor NK cell engraftment as well as the impact of missing recipient KIR ligands and the number of donor inhibitory and activating KIR genes on HCT outcomes in 282 patients (153 with HLA-matched related donors and 129 with unrelated donors) conditioned with 2 Gy TBI +/– fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Diagnoses were hematological malignancies (n=274) or solid tumors (8). Methods: NK cells were isolated from peripheral blood by flow cytometry on days 14, 28 and 42 after HCT. The proportions of cells of donor and host origin were assessed by FISH or by VNTR-PCR. High-resolution HLA-typing was performed using oligonucleotide probe and/or direct sequencing methods. Donor KIR genotyping was performed using a commercial PCR-SSP kit (Invitrogen) following manufacturers protocol. Results: High numbers of T (P=0.01) and CD34+ (P=0.009) cells in the graft, as well as lower numbers of donor inhibitory KIR genes (P=0.01) were each associated with higher levels of donor NK cell chimerism. There was a suggestion of an association between lower numbers of activating KIR genes and higher CD56 chimerism, however this was not statistically significant. NK cell chimerism levels were comparable in patients who had all KIR ligands present vs. in those who were missing any ligand, and there was no association between the specific missing ligand and NK chimerism. A day-14 NK cell chimerism level of < 50% was associated with increased risks of graft rejection (P=.009). Modeling chimerism levels as a continuous linear variable, there was no association between NK cell chimerism levels on day 14 and occurrence of grade II-IV acute GVHD. In contrast, high levels of donor NK cell chimerism on days 14–42 were associated with a lower risk of relapse (P=0.006) and better progression-free survival (P=0.003) in time-dependent analyses. The qualitative associations between donor NK cell chimerism and graft rejection, GVHD, relapse or progression-free survival did not change after adjustment for the presence of recipient KIR ligands nor after adjustment for the number of donor inhibitory or activating KIR genes. Finally, the 3-year cumulative incidence of relapse was 42% in patients who have all ligand for donor NK cell KIR, versus 38% in patients who miss one or more ligand for donor NK cell KIR (adjusted hazard ratio = 1.05; 95% confidence interval 0.65–1.68; p=0.85). Conclusions: Robust engraftment of donor NK cells correlated with low risk of graft rejection, low risk of relapse and high progression-free survival but not with acute GVHD. The clinical importance of donor KIR inhibitory and activating genes on post-transplant donor NK chimerism merits further study. Footnotes Disclosure: Off Label Use: Fludarabine, Mycophenolate mofetil, Cyclosporine. [less ▲]Detailed reference viewed: 9 (0 ULg)
Array-CGH analysis of T-ALL patients and cell lines
; ; et al
in Blood (2006, November 16), 108(11, Part 2), 195-196Detailed reference viewed: 41 (1 ULg)
New role for ATP P2X1 receptors in the control of neutrophil apoptosis and respiratory burst activity.
Faccinetto, Céline ; Lecut, Christelle ; Greimers, Roland et al
in Blood (2006), 108(11, Part 1), 1647Detailed reference viewed: 32 (12 ULg)