Constitutional platelet disorders associated with defects in FLI1, ETV6 and GATA1 transcription factors

Les thrombopénies constitutionnelles (TC) sont des maladies encore incomplètement caractérisées. Ce travail de thèse concerne les TC liées à 10 variants des gènes codant les facteurs de transcription FLI1, ETV6 et GATA1, dont 9 n’avaient jamais été décrits. Ces pathologies ont été étudiés à partir de patients recruté dans un réseau national (Centre de Référence des Pathologies Plaquettaires CRPP) et un réseau international (BRIDGE consortium).Nous montrons qu’il existe un déficit sévère en granules denses dans les plaquettes des patients porteurs de variants FLI1 du fait d’un probable défaut de biogénèse. Ce travail, et d’autres études publiées récemment, ont permis de définir la TC liée aux variants ETV6 en tant que nouveau syndrome de prédisposition aux hémopathies malignes. Les variants FLI1 s’associent à une diminution d’activité transcriptionnelle et d’accumulation nucléaire de la protéine et à des anomalies de la différenciation mégacaryocytaire. Les variants ETV6 s’associent à un défaut d’activité répressive et les mégacaryocytes dérivés des patients montrent un excès de prolifération et un défaut marqué de formation des proplaquettes. Les plaquettes de patients porteurs de variants GATA1 ont montré une expression anormale de la protéine MYH10, ce qui suggère un défaut de répression du gène MYH10 au cours de la mégacaryopoïèse. Une analyse in silico de données de ChIP-seq a ainsi montré l’existence d’une fixation de GATA1 dans le promoteur et dans un intron de MYH10 dans le mégacaryocyte.Ce projet a permis d'apporter des connaissances sur les causes génétiques, le phénotype, le diagnostic, le pronostic et les mécanismes physiopathologiques des TC.Constitutional thrombocytopenia (CT) is a group of diseases incompletely characterized. This thesis focused on CTs due to 10 variants in genes encoding the transcription factors FLI1, ETV6 and GATA1, of which 9 had never been described. These diseases were studied in French and European patients recruited using national (French national reference center for inherited platelet disorders CRPP) and international (BRIDGE consortium) networks.We showed that the platelets of patients carrying FLI1 variants harbored a severe dense granule defect probably due a biogenesis defect. Our work, associated with data published by other groups, has defined ETV6-related CT as a new hematological malignancy predisposition syndrome. FLI1 variants are associated with a decreased transcriptional activity, a decreased nuclear accumulation of the protein and abnormal megakaryocyte differentiation. ETV6 variants led to a decreased repressive activity and the megakaryocytes derived from patients showed increased proliferation and a marked defect in proplatelet formation. The platelets of GATA1 variant carriers showed aberrant expression of MYH10 protein suggesting a defective silencing of MYH10 gene during megakaryopoiesis. Consistently, in silico analysis of ChIP-seq data showed that GATA1 binds the promoter and an intronic region of the MYH10 in megakaryocytes.This project has provided insights into genetic causes, phenotype, diagnosis, prognosis and pathophysiological mechanisms of CTs

Hematopoietic stem cell transplantation for the treatment of leukocyte adhesion deficiency type III

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Pancytopenia and megaloblastic erythropoiesis reveal a novel GIF mutation

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Six‐month BNT162b2 vaccine efficacy in adolescents and young adults with cancer

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Bone marrow erythroid cell inclusions reveal congenital erythropoietic porphyria

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Bone marrow erythroid cell inclusions reveal congenital erythropoietic porphyria

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Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge

International audiencePediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around 30%. Cytogenetics is an important factor for diagnosis and indication of prognosis. The main cytogenetic abnormalities are referenced in the current WHO classification of acute myeloid leukemia, where there is an indication for risk-adapted therapy. The aim of this article is to provide an updated review of cytogenetics in pediatric AML, describing well-known WHO entities, as well as new subgroups and germline mutations with therapeutic implications. We describe the main chromosomal abnormalities, their frequency according to age and AML subtypes, and their prognostic relevance within current therapeutic protocols. We focus on de novo AML and on cytogenetic diagnosis, including the practical difficulties encountered, based on the most recent hematological and cytogenetic recommendations

BNT162b2 COVID-19 Vaccines in Children, Adolescents and Young Adults with Cancer—A 1-Year Follow-Up

International audience(1) Background: Children and young adults with cancer are poorly represented in COVID-19 vaccination studies, and long-term protection conferred by vaccination is not known. (2) Objectives: 1. To determine the adverse effects associated with BNT162B2 vaccination in children and young adults with cancer. 2. To assess its efficacy in stimulating immunological response and in preventing severe COVID-19 disease. (3) Methods: Retrospective single-center study evaluating patients aged 8 to 22 years, with cancer, who underwent vaccination from January 2021 to June 2022. ELISA serologies and serum neutralization were collected monthly from the first injection. Serologies below 26 were considered negative, while those above 264 BAU/mL were considered positive and indicative of protection. Antibodies titers were considered positive above 20. Data on adverse events and infections were collected. (4) Results: 38 patients were included (M/F = 1.7, median age 16 years), of whom 63% had a localized tumor and 76% were undergoing treatment at the time of the first vaccination. Two or three vaccine injections were administered in 90% of patients. Adverse events were mainly systemic and not severe, except for seven grade 3 toxicities. Four cancer-related deaths were reported. Median serology was negative the month following the first vaccination and became protective during the third month. At 3 and 12 months, median serology was 1778 and 6437 BAU/mL, respectively. Serum neutralization was positive in 97% of the patients. COVID-19 infection occurred despite vaccination in 18%; all were mild forms. (5) Conclusions: In children and young adults with cancer, vaccination was well tolerated and conferred effective serum neutralization. COVID-19 infections were mild, and vaccine seroconversion persisted after 12 months in most patients. The value of additional vaccination should be further established