Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes.
Robert, Isabelle ; Aussems, Marie ; Keutgens, Aurore et al
in Oncogene (2009), 28(13), 1626-1638
Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such ... [more ▼]
Constitutive nuclear factor (NF)-kappaB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-kappaB inhibitory molecules such as IkappaBalpha or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-kappaB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-kappaB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IkappaBalpha promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-kappaB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-kappaB-activating pathway. [less ▲]Detailed reference viewed: 110 (39 ULg)
Non-myeloablative transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a phase II randomized trial.
Willems, Evelyne ; Baron, Frédéric ; Baudoux, Etienne et al
in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2009), 23(3), 608-10Detailed reference viewed: 71 (34 ULg)
Prediction of response to recombinant human erythropoietin in the anemia of cancer
Beguin, Yves ;
in Nowrousian, M. R. (Ed.) Recombinant human erythropoietin (rhEPO) in clinical oncology (2nd Ed.) (2008)Detailed reference viewed: 11 (1 ULg)
Recombinant human erythropoietin therapy after allogeneic hematopoietic cell transplantation with a nonmyeloablative conditioning regimen: low donor chimerism predicts for poor response.
; Baron, Frédéric ; Willems, Evelyne et al
in Experimental hematology (2006), 34(7), 841-50
PURPOSE: After allogeneic hematopoietic stem cell transplantation with nonmyeloablative conditioning (NMHCT), many patients experience prolonged anemia and require red blood cell (RBC) transfusions. We ... [more ▼]
PURPOSE: After allogeneic hematopoietic stem cell transplantation with nonmyeloablative conditioning (NMHCT), many patients experience prolonged anemia and require red blood cell (RBC) transfusions. We enrolled 60 consecutive patients undergoing NMHCT in a phase II trial to determine the optimal utilization of recombinant human erythropoietin (rHuEPO) therapy in this setting. PATIENTS AND METHODS: The first 14 NMHCT recipients did not receive rHuEPO (control group). Nineteen patients were scheduled to start rHuEPO on day 0 (EPO group 2) and 27 patients on day 28 after the transplant (EPO group 1). RHuEPO was administered subcutaneously once weekly at a dose of 500 U/kg/wk with the aim of achieving hemoglobin (Hb) levels of 13 g/dL. The 3 groups were well balanced for major characteristics. RESULTS: During the first month (p < 0.0001) as well as days 30 to 100 (p < 0.0001) and days 100 to 180 (p < 0.0001), Hb values were higher in patients receiving rHuEPO compared to those not receiving it. However, transfusion requirements were significantly decreased only in the first month in EPO group 2 (p = 0.0169). T-cell chimerism above 60% on day 42 was the best predictor of Hb response (p < 0.0001) or Hb correction (p = 0.0217), but myeloid chimerism above 90% also predicted for Hb response (p = 0.0069). Hb response was also decreased in patients receiving CD8-depleted grafts and increased in the few patients not receiving TBI, but only in univariate analysis. CONCLUSIONS: Anemia after NMHCT is sensitive to rHuEPO therapy, but less so than after conventional allogeneic HCT. RHuEPO decreases transfusion requirements only in the first 30 days posttransplant. T-cell chimerism below 60% on day 42 impaired Hb response, suggesting possible inhibition of donor erythropoiesis by residual recipient lymphocytes. A prospective randomized trial should be performed with rHuEPO starting on the day of transplantation to assess its clinical benefit in terms of transfusion requirements and quality of life. [less ▲]Detailed reference viewed: 46 (3 ULg)
Transfusions after nonmyeloablative or reduced-intensity conditioning regimens.
Baron, Frédéric ; ; Beguin, Yves
in Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K (2006), 20(12), 2081-6Detailed reference viewed: 5 (0 ULg)
Pegfilgrastim compared with Filgrastim after autologous hematopoietic peripheral blood stem cell transplantation.
; Frere, Pascale ; et al
in Experimental hematology (2006), 34(3), 382-8
In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell (PBSC) transplantation, we compared 20 ... [more ▼]
In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell (PBSC) transplantation, we compared 20 consecutive patients with lymphoma or multiple myeloma receiving a single 6-mg dose of Pegfilgrastim on day 1 posttransplant to an historical control group of 60 patients receiving daily Filgrastim 5 microg/kg starting on day 1 posttransplant. The duration of neutropenia was similar in the Pegfilgrastim group compared with the control group. There were no differences in time to neutrophil, erythroid, or platelet engraftment nor in the incidence of fever and infections. The duration of antibiotic therapy, transfusion support, and time to hospital discharge were similar in the two groups. However, after initial hematopoietic reconstitution, we observed significantly higher values of lymphocytes (e.g., 1,660+/-1,000 versus 970+/-460 on day 80, p=0.0002), neutrophils (e.g., 3,880+/-2,030 versus 2,420+/-1,500 on day 25, p=0.0004), reticulocytes (e.g., 148,160+/-90,590 versus 87,140+/-65,920 on day 25, p<0.0001), and platelets (e.g., 210,700+/-116,090 versus 150,240+/-58,230 on day 55, p=0.0052) up to day 100 in the Pegfilgrastim group compared with the Filgrastim group. These observations had no impact on clinical outcome of the patients after day 30 due to the low incidence of infectious events after engraftment in autologous PBSC transplantation. We conclude that the effect of Pegfilgrastim administrated on day 1 posttransplant is comparable to that of daily Filgrastim on initial hematopoietic reconstitution. The possibly superior effect of Pegfilgrastim on cell counts we observed after initial engraftment should be further tested in a prospective randomized trial. [less ▲]Detailed reference viewed: 24 (1 ULg)
Efficacy of recombinant human erythropoietin therapy started one month after autologous peripheral blood stem cell transplantation.
; Baron, Frédéric ; Frere, Pascale et al
in Haematologica (2005), 90(9), 1269-70
On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment ... [more ▼]
On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment (control group). After 3 weeks, hemoglobin (p<0.0001) and serum transferrin receptor (p<0.0001) concentrations were higher in the Epo group. Hb response (+2 g/dL) was achieved in 100% vs 28% (p<0.0001) and Hb correction (> or =13 g/dL) in 70% vs 10% (p=0.0238) of the patients, respectively. This is the first randomized study showing an efficacy of erythropoietin therapy on Hb levels after autologous PBSCT. [less ▲]Detailed reference viewed: 35 (3 ULg)
Immunotherapie du cancer par minigreffe de cellules souches hematopoietiques.
Willems, Evelyne ; Baron, Frédéric ; et al
in Revue Médicale Suisse (2005), 1(30), 1973-7
Allogeneic hematopoietic stem cell transplantation (HSCT) is used for the treatment of selected haematological malignancies. Its curative potential is based on two different mechanisms, i.e. the ... [more ▼]
Allogeneic hematopoietic stem cell transplantation (HSCT) is used for the treatment of selected haematological malignancies. Its curative potential is based on two different mechanisms, i.e. the conditioning regimen and the graft-versus-host immunologic reactions. However, because of its toxicity, it is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols. These transplants are called nonmyeloablative HSCT or minitransplants. These are feasible with a relatively low transplant-related mortality even in patients up to 70 years. In addition, strong anti-tumor responses are observed in several haematological malignancies. [less ▲]Detailed reference viewed: 73 (5 ULg)