Current mechanisms of lymphomagenesis, which require at least two and/or three genetic ‘hits’ leading to the development of lymphoproliferative disease (LPD) or lymphoma. The mechanisms are shown for ‘early lesions’ post-transplant LPD (PTLD), including infectious mononucleosis (IM-), follicular hyperplasia (FH-) and plasmacytic hyperplasia (PH-) PTLDs, polymorphic (P-) PTLD, post-transplant diffuse large B-cell lymphoma (PT-DLBCL), as well as DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and DLBCL, not otherwise specified (NOS). The timeline highlights the difference in time to develop PTLD, IS-DLBCL and DLBCL, NOS after transplantation, after the start of immunosuppression or the average age for the disease onset, respectively. L-CHIP, lymphoid clonal haematopoiesis of indeterminate potential; OG, oncogene; TS, tumour suppressor.

We firstly uncovered a novel link between reduced HOPX expression, its promoter hypermethylation and increased tumour burden in patients with T-ALL, suggesting its tumour-suppressive role. Next, we induced T-ALL by transducing intracellular NOTCH1 (ICN1) into mice with either conditional knock-in at the Rosa26 locus or knockout of Hopx. We found that T-ALL development was markedly accelerated and impeded in backgrounds with low and high Hopx expression respectively. Further analysis revealed Hopx's roles in modulating the Wnt-β-catenin pathway, a pivotal regulator of the downstream Myc signalling involved in T-ALL transformation and progression.

Zandelisib, a selective, potent PI3Kδ inhibitor, demonstrated favourable outcomes in patients with relapsed or refractory follicular lymphoma in a global phase II study. This phase II study evaluated the efficacy and safety of zandelisib for relapsed or refractory follicular lymphoma or marginal zone lymphoma by a unique intermittent dosing schedule to mitigate its on-target toxicities. The objective response rate was 75.4%, with a 24.6% complete response rate. The cumulative incidence of Grade ≥ 3 AEs of special interests reached a plateau after cycle 3. Zandelisib showed a favourable benefit–risk profile for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Bortezomib plus rituximab plus bendamustine regimen is a short-time, low-cost and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia (RR-WM) patients after the first line of therapy. The deep anti-tumour activity is highlighted by an absolute increase of progression-free survival (PFS) rate in comparison to historical controls (30-month PFS of 79%), as well as by high rates of clinical response, with 30% of minimal residual disease (MRD) negativity at the end of the therapy. As expected, toxicity was mainly haematological, gastrointestinal and neurological, but required discontinuation of therapy only in few cases. MYD88 is a valid marker for WM diagnosis at baseline and can be used as marker for MRD at the end of the therapy MYD88 mutation detection in circulating cell-free DNA from plasma shows a good concordance with bone marrow. By using droplet digital polymerase chain reaction (ddPCR), molecular analysis in unsorted blood white cells is a new feasible and inexpensive assay.

HIF-2α, encoded by EPAS1, is the main transcriptional factor of EPO production in the kidney, which maintains the dynamic balance of erythropoiesis. Herein, three monoallelic EPAS1 variants from three unrelated families were identified in a paediatric anaemia cohort. Highly consistent clinical phenotypes with normocytic and normochromic anaemia, reticulocytopenia and relative deficiency of serum EPO were revealed in the patients. The HIF-2α mutants showed defects in steady-state protein abundance, nuclear localisation and binding with co-activator, which lead to impaired EPO transcriptional activation. These findings indicated monoallelic EPAS1 variants cause congenital hypoplastic anaemia depending on EPO production in a loss-of-function mechanism.

The subjectivity of morphological assessment and the overlapping pathological features of different subtypes of myeloproliferative neoplasms (MPNs) make accurate diagnosis challenging. To improve the pathological assessment of MPNs, we took both haematoxylin–eosin staining BM whole-slide images (WSI) and clinical features from 1051 MPN and non-MPN patients from seven hospitals in China, and developed artificial intelligence-assisted model based on the combination of WSI and clinical parameters for pathological diagnosis. Our model demonstrated well performance in distinguishing MPNs from non-MPN conditions and MPN subtypes. The diagnostic accuracies surpassed those of junior haematopathologists and were equivalent to seniors, providing a new perspective on the comprehensive utilization of deep learning models in MPN morphological assessment.

This study investigates the efficacy of anti-CD25 monoclonal antibody (mAb) as a potential MTX alternative. Participants were divided into two cohorts: a single-dose group (25 mg/day anti-CD25 mAb with MTX) and a double-dose group (50 mg/day anti-CD25 mAb without MTX). Herein, we demonstrated that a higher dose of humanized anti-CD25 mAb without MTX can successfully reduce CI of total aGVHD by day 100, grade III–IV aGVHD by day 100, 1-year cGVHD as well as mod/sev cGVHD. Furthermore, this regimen produced statistically significant outcomes in enhancing engraftment, reducing and alleviating OM incidence, diminishing infection rates, mitigating treatment-induced mucosal damage and improving GRFS in patients. These findings suggest that a double-dose anti-CD25 mAb regimen without MTX is a promising strategy for aGVHD prophylaxis in haplo-HSCT.

We introduce a novel CAR-T-cell engineering strategy utilizing mRNA-laden lipid nanoparticles (mRNA-LNPs) to address the challenges of viral vector-based approaches, including insertional mutagenesis and high production costs. Humanized CAR mRNA targeting CD19 was encapsulated into LNPs using microfluidic mixing, achieving efficient transfection and robust CAR expression. Engineered CAR-T cells exhibited potent cytotoxicity against leukaemic cells in vitro, demonstrated increased cytokine secretion and enhanced tumour killing in co-culture systems. In vivo studies in NSG mice with Raji cell engraftment confirmed significant tumour regression and prolonged survival, highlighting mRNA-LNP technology as a safer, scalable alternative for CAR-T therapy.

In this prospective, observational, real-world, multicentre study, we evaluated 106 patients affected by mantle cell lymphoma. The patients were treated with the anti-CD19 CAR T-cell therapy Brexucabtagene autoleucel (brexu-cel). Our study corroborated the association between in-vivo CAR T-cell expansion and progression-free survival (PFS). Moreover, refractoriness to Bruton tyrosine-kinase inhibitors (BTKi) was identified as a negative prognostic factor.

Imaging flow cytometry (IFC) combines the advantages of flow cytometry (FC) and microscopy to provide detailed morphological insights into platelets. In this study, we evaluated the performance of morphometric features for heparin-induced thrombocytopenia (HIT) diagnosis. A total of 42 patients with suspected HIT were included: 28 HIT-positive patients (tested once) and 14 HIT-negative patients (tested twice). Morphometric features such as size, shape and contrast showed significant changes between resting platelets (negative control, NaCl) and TRAP-6-activated platelets (positive control), enabling the detection of platelet activation with IFC. To diagnose HIT, donor platelet-rich plasma was mixed with patient platelet-poor plasma in the presence of increasing concentrations of heparin. Subsequently, platelets were labelled with CD62P, an internal marker of platelet activation. Measurements of area, diameter and major axis features reliably identified HIT-positive patients, with performance levels comparable to those of CD62P expression. This study highlights that IFC is a label-free, robust and efficient method for detecting platelet activation, offering a promising alternative to conventional functional assays for HIT diagnosis.

This study investigated the neurocognitive and electrophysiological effects of 1-year memantine treatment in young individuals with sickle cell disease (SCD). Assessments included Wechsler Intelligence Scale subtests and a computerized task-switching paradigm, with concurrent event-related potential (ERP) recordings taken before (T1) and after (T2) the treatment period. Results indicated improvements in processing speed, working memory and executive function, accompanied by enhanced neural efficiency during cognitive tasks. These preliminary results support the potential effectiveness of memantine in SCD and warrant further investigation.

Haemoglobin H (HbH) disease with co-inheritance of HbE mutation is frequently found in Southeast Asia. This large multicentre study with a total of 588 enrolled patients demonstrated that co-inheritance of HbE mutation was associated with a higher rate of on-demand or chronic transfusions compared to those with HbH disease alone. The impact of HbE co-inheritance was mainly observed in patients with non-deletional HbH disease. The graph shows the proportion of patients in each diagnosis group becoming transfusion-dependent at different ages.

Hydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD). HC's benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. Here, we performed bulk RNA-Seq on whole blood samples collected from 25 paediatric patients with SCD to identify genes and pathways affected by treatment with HC. Pathways related to haeme metabolism, interferon-gamma response, and interferon-alpha response were significantly downregulated at HC MTD relative to the matched pre-HC samples. Pathways linked with IL2-STAT5 signalling and TNFα signalling via NF-Kβ were observed to be up-regulated at HC MTD. These results pave the way for an improved understanding of the HbF induction-independent benefits of HC.

Description of a Type 3 erythrocytosis informative family over four generations comprising five erythrocytic members. These five members harbour two unreported prolyl hydroxylase domain 2 (PHD2) mutations L195H and E225D, lying within the catalytic domain. These mutations affect PHD2 stability, which is involved in the O₂-sensing pathway. Structural, biochemical and functional studies allow us to depict each mutation effect. Erythrocytosis ranges from asymptomatic to symptomatic. Proband experienced ischaemic stroke: She was an old smoking woman without any other genetic causes except PHD2 mutations. Clinical effect of these mutations can be inapparent, as shown in one case, maybe due to his genetic background.

In France, Germany and the United Kingdom, different bedside safety measures are implemented to prevent ABO-incompatible red cell transfusion (ABO-it). In France and Germany, in addition to the identity check, a bedside ABO compatibility test is mandatory. In the UK, the identity check is performed with or without electronic patient identification (ePID). From 2013 to 2022, similar ABO-it frequencies were observed in France and in the UK despite different bedside safety measures, whereas a higher frequency was reported for Germany in spite of similar bedside safety policies as in France. In the three countries, ABO-it mainly resulted from failures in bedside pretransfusion safety policies, erroneous patient identification and transfusion of a red cell unit intended for another patient. Current safety measures do not fully prevent ABO-it with human errors remaining the leading cause. Further implementation of effective ePID systems across the entire transfusion process applied by well-trained personnel should be considered.

As an immunogenetic disease susceptibility factor, human leucocyte antigen (HLA) class II loci involve in the pathophysiology of acquired aplastic anaemia (AA) by regulating the immune response and autoreactive T-cell-mediated haematopoietic cell death. Distinctive amino acid configurations encoded by the at-risk HLA alleles enriched in AA patients impact the immune presentation of the peptide repertoire derived from haematopoietic stem/progenitor cells. DRβ-Ala-71, DQβ-Asp-57 and DRβ-Gln-16 are discovered as crucial risk amino acid residues in HLA II class proteins on the onset of AA, as well as associated with paroxysmal nocturnal haemoglobinuria (PNH)-type cells and pathological somatic or cytogenetic mutations. DRβ-Ala-71 and DQβ-Asp-57 within the antigen-binding groove interacting with a more variable antigenic segments, may impact the repertoire of peptides presented, influence the interface HLA-antigen-T-cell receptor β (TCR β).