Haematologica最新文献

Over the past 40 years, the introduction and refinement of hydroxyurea therapy has led to remarkable progress for the care of individuals with sickle cell anemia (SCA). From initial small proof-of-principle studies to multi-center Phase 3 controlled clinical trials and then numerous open-label studies, the consistent benefits of once-daily oral hydroxyurea have been demonstrated across the lifespan. Elevated fetal hemoglobin (HbF) serves as the most important treatment response, as HbF delays sickle hemoglobin polymerization and reduces erythrocyte sickling. Increased amounts of HbF, especially when distributed across the majority of erythrocytes, improve clinical outcomes by reducing hemolytic anemia and preventing vasoocclusion, thereby ameliorating both acute and chronic-and overt and covert-complications. Additional benefits of hydroxyurea beyond HbF induction include lower neutrophil and platelet counts, reduced inflammation, and improved rheology. Toxicities of hydroxyurea in SCA are typically mild and predictable; modest cytopenia is expected and actually therapeutic, while occasional gastrointestinal and cutaneous manifestations are well-tolerated. Long-term risks of hydroxyurea for SCA are mainly theoretical but require ongoing surveillance. Accordingly, hydroxyurea should be initiated as part of standard-of-care, ideally in the first year of life. Proper dosing of hydroxyurea is critical, aiming through stepwise dose escalation to achieve modest but safe myelosuppression, with periodic adjustments for weight gain. Precision dosing using pharmacokinetics may facilitate optimal dosing without frequent dose adjustments. Although transformative and even curative therapies for SCA are emerging, hydroxyurea is the only available and accessible disease-modifying treatment that can address the global burden of disease, especially in low-resource settings within sub-Saharan Africa.

Germline variants of FLI1, essential for megakaryopoiesis, are linked to bleeding disorders, platelet aggregation defects and mild thrombocytopenia. However, the mechanisms behind these abnormalities remain unclear. This study aims to elucidate the impact of FLI1 variants on human megakaryocytes and platelets. We focused on four FLI1 variants, two of which are novel (p.G307R and p.R340C). We assessed the impact of FLI1 variants on megakaryopoiesis using single-cell RNA sequencing and defects were confirmed in patient platelets and cell lines. Results showed variants p.R337Q, p.K345E and p.R340C exhibited faulty nuclear localization and defective transcriptional activity in vitro and variants p.K345E and p.G307R affected protein stability. A total of 626 genes were differentially expressed in patient megakaryocytes, including genes associated with the platelet activation pathway. TLN1 was among the most downregulated genes, with an 88% reduction in talin-1 protein levels in FLI1 patient platelets. Analysis of chromatin immunoprecipitation sequencing data revealed FLI1-binding regions in the TLN1 gene. Luciferase reporter gene assays revealed the functional role of an intronic binding region in cooperation with GATA1. FLI1 variants were linked to reduced cooperative transcriptional activity. These findings reveal novel mechanisms underlying the pathogenicity of FLI1 variants. Defective cooperation between FLI1 variants and GATA1 may play a role in talin-1 deficiency in FLI1 patient platelets, thus contributing to platelet dysfunction. Moreover, talin-1 could serve as a biomarker for classifying the pathogenicity of FLI1 variants.

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Whereas immunotherapies have revolutionized the treatment of different solid and hematologic cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCL) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCL, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tumoral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analysis on a retrospective cohort of 43 AITL patients demonstrated a significant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the complex TME of nodal PTCL, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.