Haematologica最新文献

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The prognosis of pediatric acute myeloid leukemia (AML) remains poor compared with pediatric acute lymphoblastic leukemia (ALL); accurate diagnosis and treatment strategies based on the genomic background are strongly needed. Recent advances in sequencing technologies have identified novel pediatric AML subtypes, including BCL11B structural variants and UBTF tandem duplications (UBTF-TD), associated with poor prognosis. In contrast, these novel subtypes do not fit into the diagnostic systems for AML of the 5th edition WHO classification or International Consensus Classifications (ICC) released in 2022. In this review, we describe the current state of pediatric AML classification in the context of a new classification framework based on the findings of updated genomic profiling. Molecular categories in the new classification system are associated with unique transcriptional, mutational, and clinical characteristics, which can be leveraged for predicting clinical outcomes and developing molecular-target therapies based on the initiating driver alterations. We also highlight four high-risk subtypes of pediatric AML, namely CBFA2T3::GLIS2, BCL11B, UBTF-TD, and ETS family fusions, focusing on their disease mechanisms, clinical associations, and possible therapeutic strategies to overcome the dismal clinical outcomes associated with these alterations.

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While outcomes for pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) have improved dramatically in recent decades, relapsed and refractory disease remain a significant therapeutic challenge. This is particularly true for patients with T-cell ALL and LBL, where survival for patients with relapsed/refractory disease remains dismal. Recent efforts to comprehensively profile the genomics of T-ALL/LBL to improve understanding of disease biology have enhanced our ability to identify high-risk patients at diagnosis who are more likely to relapse and have also identified novel targets for precision medicines. Novel immunotherapies have transformed the treatment landscape for patients with B-cell ALL (B-ALL). Many immunotherapies are under investigation in clinical trials for patients with T-ALL/LBL and early results are very promising. Given these insights into disease biology and the development of targeted and immune-based treatments, it is reasonable to hope for improved patient outcomes, although challenges still exist. In this review, we summarize the present state of understanding of the risk factors for relapse of T-ALL/LBL, established treatment regimens, and the promising small molecule inhibitors and immunotherapies with the potential to revolutionize the treatment of relapsed/refractory T-ALL/LBL.

In acute myeloid leukemia (AML), leukemogenesis depends on cell-intrinsic genetic aberrations and thus, studies on AML require investigations in an in vivo setting as provided by patient derived xenografts (PDX) models. Here we report that, next to leukemic cell characteristics, recipient sex highly influences the outgrowth of AML cells in PDX models, with females being much better repopulated than males in primary as well as secondary transplantation assays. Testosterone may be the more important player since, strikingly, better engraftment was seen in castrated versus control male recipients, while ovariectomy did not significantly impair engraftment in females. Shorter time-to-engraftment and mouse survival were observed with adverse molecular risk, and respectively with high FLT3-ITD ratio mutated AML cells. Adverse risk AML furthermore showed higher percentages of phenotypic leukemic stem cells (LSCs), suggesting impaired differentiation capacity in these AML subtypes. Overall, we achieved successful repopulation with 14/23 (61%) favorable, 18/30 (60%) intermediate and 4/8 (50%) adverse risk AML cases in female recipient PDX models. Our data identify recipient sex as an important experimental confounder in leukemia PDX models, and the contribution of the sex hormones to leukemogenesis as an intriguing, underexplored research area.

Von Willebrand factor (VWF) plays a critical role in hemostasis, and emerging evidence suggests its involvement in inflammation. Our study aimed to investigate the interaction between circulating plasma VWF and neutrophils (polymorphonuclear cells, PMNs), elucidate the fate of VWF after binding, and explore its impact on neutrophil behavior. Neutrophils were isolated from the whole blood of healthy volunteers, and their interaction with plasma VWF was examined ex vivo. Immunofluorescence imaging revealed an enhanced binding of VWF to neutrophils following stimulation with inflammatory agents (PMA, TNFα, and IL-8) and exposure to shear forces, highlighting a previously unknown interaction. Furthermore, immunofluorescence images demonstrated increased co-localization of VWF with the early endosome marker EEA1 and the late endosome marker Rab7 over time, indicating the uptake of VWF by neutrophils subsequent to the binding. This was supported by a significant decrease in VWF antigen levels in the supernatant of cells after stimulation. Moreover, stimulated neutrophils exposed to purified plasma-derived VWF exhibited elevated expression of neutrophil surface markers CD45 and CD66b, indicative of altered neutrophil function related to cell adhesion, migration, and phagocytosis. These findings suggest that VWF binding can modulate neutrophil function, potentially influencing their role in immune responses and inflammation. In summary, our study provides novel insights into the complex interplay between VWF and neutrophils, shedding light on the multifaceted roles of VWF in inflammation. Importantly, we have identified neutrophils as potential cellular mediators involved in the clearance of VWF from circulation, introducing a novel mechanism for VWF removal.

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.