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1.
Am J Hematol ; 99(7): 1240-1249, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38586986

RESUMO

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.


Assuntos
Neoplasias do Sistema Nervoso Central , Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Leucaférese , Indução de Remissão , Adulto , Idoso de 80 Anos ou mais , Receptores de Antígenos Quiméricos
2.
Blood ; 136(12): 1381-1393, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32589714

RESUMO

Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here, we identify late erythroblasts as a new host cell for P falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.


Assuntos
Eritroblastos/parasitologia , Eritropoese , Interações Hospedeiro-Parasita , Malária Falciparum/fisiopatologia , Plasmodium falciparum/fisiologia , Adulto , Medula Óssea/parasitologia , Medula Óssea/fisiopatologia , Células Cultivadas , Eritroblastos/patologia , Feminino , Humanos , Malária Falciparum/parasitologia , Adulto Jovem
3.
J Clin Apher ; 37(1): 25-30, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34726791

RESUMO

BACKGROUND: The off-line extracorporeal photopheresis (ECP) procedure requires photosensitization in an external cell therapy laboratory as per the French regulatory requirement. This regulation results in higher time and costs compared with the on-line alternative performed entirely at the patient's bedside. Recently, full in situ execution of the off-line procedure has been implemented in the Pitié-Salpêtrière Hospital Hemobiotherapy Department (Paris, France). This report summarizes the center's experience regarding the organizational and costs impacts of this change compared with the on-line procedure. MATERIAL AND METHODS: ECP was broken down into stages, and several procedures were monitored prospectively in real-life settings. The total costs associated with both procedures were the sum of the fixed costs and variable costs related to all stages of the procedures, nursing-time costs, property costs, and patient-related production loss costs. RESULTS: Eight off-line ECP and fourteen on-line ECP procedures were monitored during five consecutive days. Procedure duration was not different (median 137.5 vs 154.0 minutes, P = .29). Times and costs associated with nursing were higher but offset by lower fixed costs of the off-line ECP. Total direct costs per procedure associated with using the off-line ECP were significantly lower than those of the on-line procedure (459.6 ± 7.1 EUR vs 953.8 ± 6.5 EUR; P = .0002). Similar results were observed when including the costs of patient production loss. CONCLUSIONS: As a competitive time procedure, the in situ off-line method proved to be cost-efficient by effectively offering similar patient treatment per year compared with the on-line procedure.


Assuntos
Custos e Análise de Custo , Fotoferese/economia , Fotoferese/métodos , Sistemas Automatizados de Assistência Junto ao Leito/economia , França , Humanos , Estudos Prospectivos
4.
Am J Hematol ; 96(4): 480-492, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476437

RESUMO

Efficient erythropoiesis relies on the expression of the transferrin receptor type 2 (TFR2). In erythroid precursors, TFR2 facilitates the export of the erythropoietin receptor (EPOR) to cell surface, which ensures the survival and proliferation of erythroblasts. Although TFR2 has a crucial role in erythropoiesis regulation, its mechanism of action remains to be clarified. To understand its role better, we aimed at identifying its protein partners by mass-spectrometry after immunoprecipitation in erythroid cells. Here we report the kinase MRCKα (myotonic dystrophy kinase-related CDC42-binding kinase α) as a new partner of both TFR2 and EPOR in erythroblasts. We show that MRCKα is co-expressed with TFR2, and TFR1 during terminal differentiation and regulates the internalization of the two types of transferrin receptors. The knockdown of MRCKα by shRNA in human primary erythroblasts leads to a decreased cell surface expression of both TFR1 and TFR2, an increased cell-surface expression of EPOR, and a delayed differentiation. Additionally, knockout of Mrckα in the murine MEDEP cells also leads to a striking delay in erythropoiesis, showcasing the importance of this kinase in both species. Our data highlight the importance of MRCKα in the regulation of erythropoiesis.


Assuntos
Eritropoese/fisiologia , Miotonina Proteína Quinase/fisiologia , Animais , Sistemas CRISPR-Cas , Células Cultivadas , Endocitose , Eritroblastos/citologia , Eritroblastos/metabolismo , Técnicas de Inativação de Genes , Humanos , Ferro/metabolismo , Camundongos , Miotonina Proteína Quinase/isolamento & purificação , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Receptores da Eritropoetina/metabolismo , Receptores da Transferrina/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo
5.
Haematologica ; 104(5): 907-918, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30309849

RESUMO

AMP-activated protein kinase (AMPK) is a heterotrimeric complex containing α, ß, and γ subunits involved in maintaining integrity and survival of murine red blood cells. Indeed, Ampk α1-/- , Ampk ß1-/- and Ampk γ1-/- mice develop hemolytic anemia and the plasma membrane of their red blood cells shows elasticity defects. The membrane composition evolves continuously along erythropoiesis and during red blood cell maturation; defects due to the absence of Ampk could be initiated during erythropoiesis. We, therefore, studied the role of AMPK during human erythropoiesis. Our data show that AMPK activation had two distinct phases in primary erythroblasts. The phosphorylation of AMPK (Thr172) and its target acetyl CoA carboxylase (Ser79) was elevated in immature erythroblasts (glycophorin Alow), then decreased conjointly with erythroid differentiation. In erythroblasts, knockdown of the α1 catalytic subunit by short hairpin RNA led to a decrease in cell proliferation and alterations in the expression of membrane proteins (band 3 and glycophorin A) associated with an increase in phosphorylation of adducin (Ser726). AMPK activation in mature erythroblasts (glycophorin Ahigh), achieved through the use of direct activators (GSK621 and compound 991), induced cell cycle arrest in the S phase, the induction of autophagy and caspase-dependent apoptosis, whereas no such effects were observed in similarly treated immature erythroblasts. Thus, our work suggests that AMPK activation during the final stages of erythropoiesis is deleterious. As the use of direct AMPK activators is being considered as a treatment in several pathologies (diabetes, acute myeloid leukemia), this observation is pivotal. Our data highlighted the importance of the finely-tuned regulation of AMPK during human erythropoiesis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diferenciação Celular , Eritroblastos/citologia , Eritropoese , Regulação Enzimológica da Expressão Gênica , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Adulto , Animais , Apoptose , Autofagia , Células Cultivadas , Ativação Enzimática , Eritroblastos/metabolismo , Humanos , Camundongos , Camundongos Knockout , Fosforilação , RNA Interferente Pequeno/genética
7.
J Clin Apher ; 33(1): 5-13, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28455878

RESUMO

Plerixafor (Mozobil) in combination with granulocyte colony-stimulating factor (G-CSF) has shown to increase mobilization of peripheral blood stem cells (PBSC) as compared to G-CSF alone in patients undergoing autologous stem cell transplantation (ASCT). However, up to 25% of patients treated with G-CSF alone still fail mobilization. Adding plerixafor to poor mobilizers allows to rescue these patients from mobilization failure and to reduce the number of apheresis sessions. The goal of this retrospective study was to capture the impact of plerixafor on treatment outcome and on apheresis department efficiency. The latter was measured in terms of time-slots lost, that is, the number of apheresis sessions scheduled but not carried out due to poor mobilization, and the number of elective apheresis sessions performed for patients undergoing extracorporeal photopheresis (ECP). Hospital records of patients treated before and after introduction of plerixafor were collected and analyzed. With plerixafor, the mobilization failure rate dropped from 12% to 4% and the mean number of time-slots lost per patient dropped from 1.39 to 0.89. Additional drug costs due to plerixafor were partially balanced by a reduction in apheresis sessions, resulting in an additional cost of 759€ per ASCT candidate. More importantly, with the use of plerixafor, the availability of time-slots turned from erratic to predictable such that freed capacity could be dedicated to other apheresis procedures. As a result, the number of ECP sessions increased from 0 in 2005 to 685 sessions in 2014.


Assuntos
Remoção de Componentes Sanguíneos/estatística & dados numéricos , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Hospitais/normas , Benzilaminas , Remoção de Componentes Sanguíneos/economia , Ciclamos , Quimioterapia Combinada/normas , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Compostos Heterocíclicos/economia , Compostos Heterocíclicos/farmacologia , Humanos , Estudos Retrospectivos
8.
J Clin Apher ; 32(6): 474-478, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28419561

RESUMO

INTRODUCTION: The Pitié Salpêtrière Hospital Hemobiotherapy Department, Paris, France, has been providing extracorporeal photopheresis (ECP) since November 2011, and started using the Therakos® CELLEX® fully integrated system in 2012. This report summarizes our single-center experience of transitioning from the use of multi-step ECP procedures to the fully integrated ECP system, considering the capacity and cost implications. MATERIALS AND METHODS: The total number of ECP procedures performed 2011-2015 was derived from department records. The time taken to complete a single ECP treatment using a multi-step technique and the fully integrated system at our department was assessed. Resource costs (2014€) were obtained for materials and calculated for personnel time required. Time-driven activity-based costing methods were applied to provide a cost comparison. RESULTS: The number of ECP treatments per year increased from 225 (2012) to 727 (2015). The single multi-step procedure took 270 min compared to 120 min for the fully integrated system. The total calculated per-session cost of performing ECP using the multi-step procedure was greater than with the CELLEX® system (€1,429.37 and €1,264.70 per treatment, respectively). CONCLUSIONS: For hospitals considering a transition from multi-step procedures to fully integrated methods for ECP where cost may be a barrier, time-driven activity-based costing should be utilized to gain a more comprehensive understanding the full benefit that such a transition offers. The example from our department confirmed that there were not just cost and time savings, but that the time efficiencies gained with CELLEX® allow for more patient treatments per year.


Assuntos
Custos e Análise de Custo , Fotoferese/métodos , Doença Enxerto-Hospedeiro/terapia , Pessoal de Saúde/economia , Humanos , Fotoferese/economia , Estudos Retrospectivos , Fatores de Tempo
9.
Eur J Haematol ; 94(1): 12-22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24797118

RESUMO

The use of autologous haematopoietic stem cell transplantation (ASCT) has increased considerably in lymphoid malignancies in the last decade, and it is now considered as the standard of care in particular circumstances. This review aims to present an overview of the current situation with ASCT in lymphoid malignancies in Europe, in terms of both current use and issues. It will also look briefly at ASCT in rarer haematological malignancies and at the future. It is intended as a reflection of opinion from selected centres in Europe and as an aid to understanding for those who are new to the area. The review is based on a series of four preceptorship meetings held in Europe in 2013.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Linfoide/terapia , Linfoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Europa (Continente) , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Leucemia Linfoide/diagnóstico , Linfoma/diagnóstico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante , Transplante Autólogo
11.
Transfusion ; 51(8): 1769-78, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21332732

RESUMO

BACKGROUND: Allogeneic donor natural killer (NK)-cell infusion (NK-DLI) is a promising immunotherapy for patients with hematologic disorders. CASE REPORT: This report describes the case of a patient who received a single haploidentical NK-DLI for a relapse of acute myeloid leukemia (AML) after haploidentical hematopoietic stem cell transplantation. He underwent a cytoreductive, immunosuppressive regimen before NK-DLI and received high-dose interleukin-2 in vivo for 8 weeks afterward. RESULTS: No major adverse effect was observed. Prospective phenotypic and functional studies of the NK cells showed major expansion of infused NK cells and, more importantly, of the alloreactive KIR2DL1+KIR2DL2/DL3-NKG2A- subset, which reached 117×10(6) cells/L on Day +14 after NK-DLI, the greatest expansion of infused alloreactive NK cells reported so far. Infused NK cells conserved their lytic capacities against K562 target cells and primary AML-mismatched blasts. CONCLUSION: We review the literature to clarify these data and to detail the indications for allogeneic NK-DLI, the criteria for determining the most suitable donor, the types of conditioning regimens, and the procedures for selecting and activating NK cells.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/terapia , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Imunoterapia Adotiva/métodos , Células K562 , Leucemia Mieloide Aguda/imunologia , Masculino , Recidiva , Transplante Homólogo
13.
Transfusion ; 50(12): 2649-59, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20576009

RESUMO

BACKGROUND: Some patients demonstrate delayed recoveries after autologous hematopoietic stem cell transplantation despite infusion of an adequate number of CD34+ cells/kg and clinically stable status. Factors considered being possible predictors of this outcome in this context were explored. STUDY DESIGN AND METHODS: A total of 246 patients were evaluated in terms of engraftment. Delayed recovery was defined by white blood cell recovery time exceeding mean+1 SEM. Clinical factors and graft characteristics were examined. Comparisons between patients with normal or delayed engraftment were made. Proinflammatory cytokines and proteolytic enzyme quantification and CXCR4+ and CD44+ cell enumeration were performed on peripheral hematopoietic stem cells (PHSC) product samples of patients with delayed engraftment and patients with usual engraftment time. RESULTS: Sixteen patients, who received at least 3 × 10(6) CD34+ cells/kg without known clinical factors likely to affect engraftment, demonstrated a delayed recovery time of over 20 days. Some graft variables were found to be significantly increased in these patients by univariate analysis. One variable was the total number of nucleated cells cryopreserved and infused. Among the nucleated cells, the absolute number of granulocytes before and after cryopreservation also differed significantly between the two groups. A multivariate analysis showed that the main predictive factor for delayed recovery was the number of nucleated cells in the graft (p=0.0044). The influence of contaminating cells might be related to the release of elastase, matrix metalloproteinase-9, interleukin (IL)-1ß, and IL-6 involved in stem cell homing. CONCLUSION: Therefore, the numeration of total nucleated cells and granulocytes should be considered as a possible quality control variable of PHSCs submitted for cryopreservation.


Assuntos
Função Retardada do Enxerto/etiologia , Sobrevivência de Enxerto/fisiologia , Transplante de Células-Tronco Hematopoéticas , Contagem de Leucócitos , Leucócitos/fisiologia , Adulto , Idoso , Antígenos CD34/metabolismo , Função Retardada do Enxerto/sangue , Feminino , Sobrevivência de Enxerto/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Transfusão de Leucócitos , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica/imunologia , Recuperação de Função Fisiológica/fisiologia , Transplante Autólogo/reabilitação
14.
Oncogenesis ; 9(10): 94, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093450

RESUMO

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and L-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.

15.
Bone Marrow Transplant ; 55(12): 2254-2260, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32447348

RESUMO

Mobilization of peripheral blood stem cells (PBSC) can be performed using plerixafor, which is expensive, or high-dose cyclophosphamide (HDCy). We hypothesized that the overall cost of mobilization with plerixafor might not be greater if the cost of complication management was considered. We performed a cost analysis of these two strategies. This multicentric observational study recruited patients with myeloma who underwent a first PBSC mobilization. We considered direct medical costs, including hospitalization, mobilization agents, apheresis, and supportive treatments. We included 111 patients, 54 and 57 in the HDCy and plerixafor groups, respectively. Cost of mobilization with HDCy was 5097 ± 2982€ vs. 10958 ± 1789€ for plerixafor (p < 0.0001). Cost of agents used was 1287 ± 779€ vs. 6552 ± 509€, respectively (p = 0.0009). The mean number of days of hospitalization was 2 and 2.1 days, respectively (p = 0.035). All patients achieved the minimum PBSC collection target (p = 1.0); however, ASCT was performed with HDCy in 67% patients and with plerixafor in 86% (p = 0.02). Plerixafor mobilization incurred a greater cost, mostly due to the greater cost of the drug. Hospitalization length in the two groups was similar in our series. Interestingly, plerixafor appeared to be a very effective and safe mobilizing approach translating into a greater ASCT success.


Assuntos
Compostos Heterocíclicos , Mieloma Múltiplo , Células-Tronco de Sangue Periférico , Ciclofosfamida , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Humanos , Mieloma Múltiplo/terapia
16.
Int J Oncol ; 35(3): 569-81, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19639177

RESUMO

Cytotoxic chemotherapy is ineffective in metastatic renal cancer. However, systemic administration of interleukin 2 (IL-2) or infusion of dendritic cells (DCs) loaded with tumor extracts can lead to some response rates with concomitant survival improvements. We report the results of a phase I-II pilot study combining DCs and IL-2 where six patients were included. DCs were derived from bone marrow CD34+ cells and loaded with autologous tumor extracts. CD34-DC vaccines were infused subcutaneously at day 45, 52, 59, 90 and 120 following surgery in combination with IL-2, that was subsequently administrated after the 3rd and 4th DC vaccinations. Preparation of tumor extracts and CD34-DCs were satisfactory in all patients but one. Due to rapid tumor progression, one patient was excluded before vaccination. In the 4 remaining patients, two received 3 vaccinations, while the 2 others received 5 vaccinations and the full IL-2 treatment. No adverse effect due to the vaccinations was observed. A specific immune response against autologous tumor cells was observed in the 2 patients who completed the treatment. Interestingly, these 2 patients had a more prolonged survival than the patients receiving 3 vaccinations. Importantly, a transient and massive increase of circulating natural regulatory T-cells (nTregs) was evidenced in 3 patients following IL-2 administration. Overall, the use of CD34-DC vaccines is feasible, safe and non-toxic. A specific anti-tumor immune response can be detected. However, our data highlights that IL-2 is a potent inducer of nTregs in vivo and as such may have a negative impact on cancer immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Renais/terapia , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Antígenos CD34/imunologia , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Imunofenotipagem , Imunoterapia/métodos , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/efeitos dos fármacos
17.
Cancer Discov ; 9(6): 796-811, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31018969

RESUMO

The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. SIGNIFICANCE: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.This article is highlighted in the In This Issue feature, p. 681.


Assuntos
Regulação da Expressão Gênica , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismo , Animais , Azepinas/farmacologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Proliferação de Células , Humanos , Lenalidomida/farmacologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Motivos de Nucleotídeos , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transativadores/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Macroglobulinemia de Waldenstrom/diagnóstico
18.
Bone Marrow Transplant ; 53(3): 246-254, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29255168

RESUMO

High-dose chemotherapy alongside peripheral blood stem cell (PBSC) infusion has become the standard of care in different hematologic malignancies. The goal of PBSC mobilization is to allow collection of sufficient CD34+ cells to proceed to transplantation. The current mobilization regimen with granulocyte colony-stimulating factor (G-CSF), alone or in combination with chemotherapy, still fails in 10-25% of patients. Plerixafor is able to rescue most of these patients from mobilization failure. In this study, we investigated the impact of plerixafor on the cost and time spent on apheresis in patients who were considered poor mobilizers, with <20 × 106/µl peripheral CD34+ cells after mobilization but prior to apheresis. Patient hospital records from ten centers in three European countries were reviewed and compared during two time periods, namely prior and after plerixafor introduction to the market. During the plerixafor period, patients spent less time on apheresis (350 vs. 461 min). Poor mobilizers given plerixafor collected more CD34+ cells during the first apheresis session, leading to a decrease in the average number of apheresis sessions needed. The total apheresis yield was unaffected. This analysis shows that the use of plerixafor lessens the time-effort associated with the management of poor mobilizers and reduces apheresis costs.


Assuntos
Mobilização de Células-Tronco Hematopoéticas/normas , Compostos Heterocíclicos/uso terapêutico , Linfoma não Hodgkin/terapia , Adulto , Idoso , Antígenos CD34/sangue , Benzilaminas , Remoção de Componentes Sanguíneos/economia , Ciclamos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Fatores de Tempo , Falha de Tratamento
20.
Haematologica ; 91(8): 1121-5, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16885054

RESUMO

We postulated that high-dose chemotherapy (HDC) followed by peripheral autologous hematopoietic stem cell transplantation might help to control refractory central nervous system (CNS) histiocytic disorders. Six patients with histiocytic CNS involvement were treated in this way. Two patients achieved non-active disease status, although one relapsed at 84 months. Two patients had regressive disease, one of whom progressed at 21 months. One patient had progressive disease at 14 months. One patient had extra-CNS progression but CNS regression. After a median follow-up of 22.4 months, only one of the six patients still has non-active disease. Treatment was effective on craniofacial and space-occupying brainstem lesions, and was ineffective on neurodegenerative lesions.


Assuntos
Histiocitose/tratamento farmacológico , Histiocitose/terapia , Adulto , Terapia Combinada , Relação Dose-Resposta a Droga , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Autólogo , Resultado do Tratamento
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