0000000000969483
AUTHOR
Olivier Hermine
The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70.
International audience; Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome that exhibits an erythroid-specific phenotype. In at least 70% of cases, DBA is related to a haploinsufficient germ line mutation in a ribosomal protein (RP) gene. Additional cases have been associated with mutations in GATA1. We have previously established that the RPL11+/Mut phenotype is more severe than RPS19+/Mut phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11+/Mut erythroid progenitors. The HSP70 protein is known to protect GATA1, the major erythroid transcription factor, from caspase-3 mediated cleavage during normal erythroid differentiation.…
Evidence for Three Distinct Classes of Phenotype Severity in Beta-Thalassaemia
Background: Classification of phenotype severity in patients with beta-thalassaemia has so far relied mainly on expert opinion using parameters of genotype, clinical features at diagnosis, and transfusion requirement. The aim of this study was to use a large dataset of patients with beta-thalassaemia and evaluate a classification system based on onset variables agreed on by an international expert group, including age at diagnosis, at first transfusion, and at first iron chelation. Methods: A retrospective dataset of 7910 patients with homozygous or compound heterozygous beta-thalassaemia was used and subjected to cluster and classification analysis starting with the onset variables. Result…
A role for caspases in the differentiation of erythroid cells and macrophages
Several cysteine proteases of the caspase family play a central role in many forms of cell death by apoptosis. Other enzymes of the family are involved in cytokine maturation along inflammatory response. In recent years, several caspases involved in cell death were shown to play a role in other cellular processes such as proliferation and differentiation. In the present review, we summarize the current knowledge of the role of caspases in the differentiation of erythroid cells and macrophages. Based on these two examples, we show that the nature of involved enzymes, the pathways leading to their activation in response to specific growth factors, and the specificity of the target proteins th…
Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder.
International audience; BACKGROUND & AIM:Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality.METHODS:A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Patholo…
Role of GATA-1 and HSP70 in the Dyserythropoiesis of Early Myelodysplastic Syndromes.
Abstract Abstract 3823 Poster Board III-759 Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell disorders characterized by a hypercellular dysplastic bone marrow (BM) with peripheral blood cytopenias, mainly anemia. Early MDS with less than 10% BM blasts which belong in most cases to low and intermediate-1 (int-1) risk groups according to the International Prognostic Scoring System (IPSS), usually demonstrate dyserythropoiesis. The growth of erythroid progenitors is altered, with increased caspase activation leading to excessive cell death, and cellular dysplasia characterized, in liquid culture of CD34+-derived erythroid progenitors, by a delayed expression of the gly…
Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis
International audience; Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were…
HSP27 controls GATA-1 protein level during erythroid cell differentiation.
AbstractHeat shock protein 27 (HSP27) is a chaperone whose cellular expression increases in response to various stresses and protects the cell either by inhibiting apoptotic cell death or by promoting the ubiquitination and proteasomal degradation of specific proteins. Here, we show that globin transcription factor 1 (GATA-1) is a client protein of HSP27. In 2 models of erythroid differentiation; that is, in the human erythroleukemia cell line, K562 induced to differentiate into erythroid cells on hemin exposure and CD34+ human cells ex vivo driven to erythroid differentiation in liquid culture, depletion of HSP27 provokes an accumulation of GATA-1 and impairs terminal maturation. More spec…
Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes.
Abstract Normal human erythroid cell maturation requests the transcription factor GATA-1 and a transient activation of caspase-3, with GATA-1 being protected from caspase-3–mediated cleavage by interaction with the chaperone heat shock protein 70 (Hsp70) in the nucleus. Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA-1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70…
Hematopoietic stem-cell transplantation for advanced systemic mastocytosis
Purpose Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. Patients and Methods In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1)…
Treatment for patients with relapsed/refractory mantle cell lymphoma: European-based recommendations
International audience; Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy, but the disease inevitably relapses and often follows an aggressive course. Here, clinical study results published since 2008 for patients with relapsed/refractory MCL were reviewed to compare available evidence for treatment guidance. Most trials identified were non-randomized, phase II studies performed at a limited number of sites, and many evaluated MCL as one of multiple non-Hodgkin lymphoma subtypes. Additional randomized, comparative trials are needed. Treatment selection generally depends on patient need, age and fitness, time of relapse, and line of therapy. Combina…
HSP70 sequestration by free α-globin promotes ineffective erythropoiesis in β-thalassaemia
International audience; β-Thalassaemia major (β-TM) is an inherited haemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of haemoglobin, leading to the accumulation of free α-globin chains that form toxic aggregates. Despite extensive knowledge of the molecular defects causing β-TM, little is known of the mechanisms responsible for the ineffective erythropoiesis observed in the condition, which is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of matur…
HSP70, the Key to Account for Erythroid Tropism of Diamond-Blackfan Anemia?
Abstract Diamond-Blackfan anemia (DBA) was the first ribosomopathy identified and is characterized by a moderate to severe, usually macrocytic aregenerative anemia associated with congenital malformations in 50% of the DBA cases. This congenital rare erythroblastopenia is due to a blockade in erythroid differentiation between the BFU-e and CFU-e stages. The link between a haploinsufficiency in a ribosomal protein (RP) gene that now encompass 15 different RP genes and the erythroid defect is still to be fully defined. Recently, mutations in TSR2 and GATA1 genes have been identified in a few DBA families. The GATA1 gene encodes for the major transcription factor critical for erythropoiesis an…
Persistent Coronavirus Disease 2019 (COVID-19) in an Immunocompromised Host Treated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Specific Monoclonal Antibodies
International audience; No abstract available
XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia
β-thalassemia major (β-TM) is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of hemoglobin, leading to the accumulation of free a-globin chains that aggregate and cause ineffective erythropoiesis. We have previously demonstrated that terminal erythroid maturation requires a transient activation of caspase-3 and that the chaperone Heat Shock Protein 70 (HSP70) accumulates in the nucleus to protect GATA-1 transcription factor from caspase-3 cleavage. This nuclear accumulation of HSP70 is inhibited in human β-TM erythroblasts due to HSP70 sequestration in the cytoplasm by free a-globin chains, resulting in maturation arrest and apoptosis. Like…
Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
International audience; BACKGROUND: Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. METHODS: 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohn's disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine expos…
Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress.
Abstract Background Mastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis. Objective To demonstrate a possible relationship between negative emotionality in mastocytosis and leukocyt…
XPO1 (Exportin-1) Is a Major Regulator of Human Erythroid Differentiation. Potential Clinical Applications to Decrease Ineffective Erythropoiesis of Beta-Thalassemia
Abstract Background We and others have shown that normal human erythroid cell maturation requires a transient activation of caspase-3 at late stages of maturation (Zermati et al, J Exp Med 2001). We further documented that, in human erythroblasts, the chaperone HSP70 is constitutively expressed and, at late stages of maturation, translocates into the nucleus and protects GATA-1, the master transcriptional factor critical for erythropoiesis, from caspase-3 cleavage (Ribeil et al, Nature 2007). During the maturation of human β-TM erythroblasts, HSP70 is sequestrated by excess of α-globin chains in the cytoplasm and as a consequence, GATA-1 is no longer protected from caspase-3 cleavage result…