RESUMEN
OBJECTIVE: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT). STUDY DESIGN: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units. RESULTS: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents. CONCLUSIONS: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.
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Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/epidemiología , Leucemia Mieloide Aguda/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adolescente , Niño , Preescolar , Femenino , Francia , Humanos , Incidencia , Lactante , Recién Nacido , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/terapia , Masculino , Estudios RetrospectivosAsunto(s)
COVID-19 , Atención a la Salud , Neoplasias , SARS-CoV-2 , Adolescente , COVID-19/epidemiología , COVID-19/terapia , Niño , Preescolar , Femenino , Francia/epidemiología , Humanos , Lactante , Masculino , Oncología Médica , Neoplasias/epidemiología , Neoplasias/terapia , Pediatría , Guías de Práctica Clínica como Asunto , Sociedades MédicasAsunto(s)
Anemia de Células Falciformes/complicaciones , Infecciones por Coronavirus/epidemiología , Leucemia de Células B/complicaciones , Neumonía Viral/epidemiología , Adolescente , Anemia de Células Falciformes/terapia , Betacoronavirus , COVID-19 , Niño , Preescolar , Femenino , Francia , Hematología , Trasplante de Células Madre Hematopoyéticas , Humanos , Huésped Inmunocomprometido , Unidades de Cuidados Intensivos , Leucemia de Células B/tratamiento farmacológico , Leucemia de Células B/virología , Masculino , Oncología Médica , Pandemias , Pediatría , Factores de Riesgo , SARS-CoV-2 , Adulto JovenRESUMEN
Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1α (HIF1α), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1α signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis.
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Hipoxia , Transducción de Señal , Masculino , Humanos , Ratones , Animales , Tetraspanina 29/genética , Tetraspanina 29/metabolismo , Adhesión Celular , OxígenoRESUMEN
Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19.
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COVID-19/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Antivirales/uso terapéutico , COVID-19/diagnóstico , Prueba de Ácido Nucleico para COVID-19 , Vacunas contra la COVID-19/uso terapéutico , Instituciones Oncológicas , Niño , Quimioterapia de Consolidación , Interacciones Farmacológicas , Francia/epidemiología , Humanos , Quimioterapia de Inducción/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Recurrencia , Medición de Riesgo , Sociedades Médicas , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. METHODS: We worked with BCP-ALL mononuclear bone marrow patients' cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. RESULTS: We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients' cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located - 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. CONCLUSIONS: Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein.
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Antineoplásicos/farmacología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Péptidos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Represoras/metabolismo , Antineoplásicos/química , Línea Celular Tumoral , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Péptidos/química , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Proteínas Represoras/química , Proteínas Represoras/genética , Activación Transcripcional/efectos de los fármacosRESUMEN
Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.