Blood advances最新文献

Abstract: Chronic myelomonocytic leukemia (CMML) is characterized by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in ≤30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. DNA damage, R-loop formation, and double-strand DNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells. Collectively, our findings show a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.

Abstract: Sickle cell disease (SCD) is an inherited red blood cell disorder with significant complications, including vaso-occlusive crisis (VOC), the most common cause of emergency department (ED) visits and hospitalizations. Pain in children with SCD is often underestimated. We evaluated the impact of a standardized institutional nurse-initiated ED SCD pain protocol, using intranasal (IN) fentanyl (INF) as the initial agent, on hospital admission rates. We conducted a preintervention/postintervention study of patients with SCD (aged 0-21 years) presenting to a quaternary pediatric ED for uncomplicated VOC pain from June 2015 to December 2019. Overall, 162 patients accounted for 471 ED visits in the preintervention period and 80 patients accounted for 162 visits in the postintervention period. After intervention, hospitalization rates (P = .0017) and inpatient length of stay (P = .0019) decreased, but median pain scores at presentation (P = .0047) and discharge (P = .1451) remained comparable. The time to initial analgesia dose significantly improved in the postintervention (P< .0001), along with the time from physician order to initial analgesia administration (P = .0005). IV and IN analgesia use rose significantly in the postintervention (odds ratio, 4.7; P< .0001), with INF being the preferred analgesic agent (61%) and a corresponding reduction in oral analgesic use (P< .0001). In an ad hoc sustainability analysis, INF use remained high and time to first dose was sustained. Implementing a standardized ED SCD pain protocol improved timeliness and consistency in analgesia administration and decreased overall hospitalization rates. This study also highlights the role of INF as an effective initial analgesic within standardized ED protocols for pediatric VOC.

Abstract: Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg type (PCDLBCL-LT) is a rare subset of DLBCL that exhibits genetic features shared with LBCL of immune-privileged sites (notably the MYD88L265P mutation) and is enriched in tumor-associated macrophages expressing M2 markers. Using a unique PCDLBCL-LT cell line (ARSI cell line) developed in our institute, we sought to mechanistically decipher the interplay between lymphoma cells and macrophages. We demonstrate that ARSI cells induce phenotypic, transcriptional, and functional changes in macrophages obtained from primary monocytes and THP-1 cell line. These changes do not require cell-cell contact, and proteome analysis of ARSI secretome reveals high concentration of several cytokines and chemokines known to affect macrophages, including interleukin-10 (IL-10). We then demonstrate that IL-10/Interleukin 10 receptor subunit alpha (IL-10RA) interaction blockade inhibits macrophage polarization induced by tumor cells. These findings are reproduced when macrophages are cocultured with PCDLBCL-LT cells from different patient-derived xenografts. However, among 4 other DLBCL cell lines, only the MYD88-mutated OCI-Ly3 cell line exhibits similar effects, which highlights the variability of macrophage interplays and led us to hypothesize that macrophage shaping, beyond the cutaneous localization, may rely on specific genetics of tumor cells. Finally, we reveal that macrophages enhance tumor cell proliferation and promote resistance to doxorubicin in coculture. In conclusion, these results confirm the robustness of this model to study lymphoma cell and macrophage interplays, underline the critical role of IL-10 in lymphoma microenvironment modeling, and may contribute to better defining its specificities in an era of rising microenvironment-targeted therapies.

Abstract: Ineffective erythropoiesis and the resulting anemia are the main characteristics of myelodysplastic syndromes (MDS). Drugs designed to promote erythropoiesis in patients with MDS include erythropoiesis-stimulating agents, such as recombinant human erythropoietin, and transforming growth factor β inhibitors, such as luspatercept, which is approved for the treatment of anemia associated with MDS or β-thalassemia. However, these types of drugs are ineffective in some patients and fail to elicit durable responses in others, underscoring the need for additional therapeutic targets. Here, we sought to define the role of ubiquitin-conjugating enzyme E2O (UBE2O), which remodels the proteome during late erythroid differentiation, in the pathogenesis of ineffective erythropoiesis in the setting of MDS and investigate its potential as a therapeutic target for improving erythropoiesis. UBE2O expression was analyzed in K562 leukemic cells and bone marrow samples from patients with MDS before and after treatment with erythropoietin and luspatercept. Bioinformatic analysis identified a GATA1 binding motif on the UBE2O promoter region, and chromatin immunoprecipitation validated the interaction. Our findings demonstrate that GATA1 binds to the UBE2O promoter, thereby regulating UBE2O transcription and expression. Although further studies are needed to explore the implications of UBE2O in MDS treatment, our work provides potential strategies for novel therapeutic approaches in MDS.

Abstract: Treatment for von Willebrand disease (VWD), the most common inherited bleeding disorder, has advanced considerably since its initial description by Erik von Willebrand who first described a family in the Åland Islands with severe bleeding. Infusion of von Willebrand factor (VWF)-containing concentrates continues to serve as the foundation of management, in addition to desmopressin, hormonal therapies, and antifibrinolytic agents such as tranexamic acid. Recent advancements in VWD management are underscored by the publication of evidence-based international guidelines addressing critical aspects such as VWF prophylaxis, the use of anticoagulants and antiplatelet agents for cardiovascular disease, and comprehensive management during surgical as well as obstetric and gynecologic scenarios. This review provides an overview of modern treatment strategies, discusses management in special populations, and explores emerging therapies and future directions for improving VWD care.

Abstract: Adaptive sampling (AS), a computational enrichment method developed for Oxford Nanopore Technologies sequencing platforms, offers a promising advance in molecular blood group diagnostics. By leveraging long-read sequencing, AS has the potential to accurately resolve complex structural variants in the RH and MNS blood group systems, while characterizing the entire blood group genome through a simple, fast and locus-adjustable protocol. As proof-of-principal, we evaluated the performance of AS using 5 samples with suspected complex variants in the RH and MNS systems, unresolved by standard immunohematological methods. Samples were sequenced on a PromethION P2 Solo with up to 2 samples per flowcell, generating 37.0 to 52.4 gigabases of data with mean on-target coverages of 18.9× to 53.4×, allowing reliable variant detection. Hybrid alleles were characterized using a de novo assembly approach, whereas variants in nonrecombinant regions were analyzed using both a custom in-house and the EPI2ME reference-based workflow. With reference to field-specific allele collections, 10% to 15% of detected alleles contained novel nonsynonymous single-nucleotide variants (SNVs) or unreported exonic SNV combinations. All suspected hybrid alleles were successfully assembled and identified as GYP∗401.02, RHD∗03N.01, and RHD∗01EL.44, representing, to our knowledge, the first fully characterized haplotypes for these variants publicly available. Overall, AS showed significant potential for advancing blood group genomics by enabling high-resolution, full-gene analysis. Its ability to support high-throughput donor genotyping and precise patient-donor matching may reduce the risk of alloimmunization and delayed hemolytic transfusion reactions, particularly in patients who receive chronic transfusions. These findings highlight AS as a powerful tool for both research and clinical applications in transfusion medicine.

Multicolor flow cytometry (MFC) is widely used for measurable residual disease (MRD) detection in acute myeloid leukemia (AML), currently recommended to perform on bone marrow (BM) aspirate only. However, BM aspiration is invasive and sometimes inadequate, whereas peripheral blood (PB) offers a patient-friendly practical alternative. We first analyzed 53 paired PB and BM samples (30 MRD-negative, 23 MRD-positive) and observed 100% concordance with strong correlation (r=0.945, p<0.001). The assay was then prospectively evaluated in 118 patients, including 63 newly diagnosed AML in post-induction (24 intensive and 30 less intensive) remission with results corroborated by molecular, cytogenetic, and follow-up data. PB MRD was positive in 26, negative in 86, and inadequate in 6, yielding 95% adequacy and 98% concordance with BM. Using BM as reference, PB testing showed 96% sensitivity, 99% specificity, 96% positive predictive value, and 99% negative predictive value. Although PB MRD levels were lower than BM (median 0.17% vs 0.84%, p=0.002), correlation was significant (r=0.6, p=0.003). Importantly, PB MRD positivity predicted relapse-free and overall survival in the full cohort (p<0.01 for both) and also post-induction subgroup (p=0.0708 and p=0.0021 respectively). These findings demonstrate that PB MFC-MRD testing is feasible, robust, and clinically informative, supporting PB as a promising complementary specimen for MRD assessment.