Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.

FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML), yet its kinase-independent mechanisms remain unclear. To investigate kinase-independent immunosuppressive mechanisms in FLT3-ITD AML, we integrated single-cell RNA sequencing from two public datasets and multiparameter flow cytometry data from 104 primary patient samples, identifying profound CD8+ T cell exhaustion as a hallmark of the FLT3-ITD immune microenvironment. Mechanistically, FLT3-ITD acts as a mutation-specific scaffold that assembles a ternary complex with PKCι and STAT1, as demonstrated by co-immunoprecipitation and intracellular colocalization. This complex enables PKCι-mediated phosphorylation of STAT1 specifically at serine 727 (S727), driving CD276 transcription independent of the canonical tyrosine 701 (Y701) site. Chromatin immunoprecipitation, electrophoretic mobility shift, promoter-reporter assays, and phosphosite-mutant constructs confirmed that S727 phosphorylation is necessary and sufficient for CD276 transactivation. Multiplex immunohistochemistry of patient bone marrow validated co-elevation of pS727-STAT1 and CD276 in FLT3-ITD blasts, accompanied by CD8+ T cell depletion. Functionally, CD276 upregulation induced profound CD8+ T cell exhaustion, characterized by reduced cytotoxicity, impaired proliferation, diminished IFN-γ production and elevated inhibitory checkpoints expression. Targeting CD276 restored CD8+ T cell function by 1.2-1.7-fold (cytotoxicity), 1.4-1.7-fold (proliferation), 1.5-1.8-fold (IFN-γ secretion) and 25.4%-67.6% (checkpoints expression) in ex vivo co-culture. In patient-derived xenograft models, co-treatment with FLT3i (quizartinib) and CD276-targeting agents led to 72.9%-80.4% tumor burden reduction and enhanced CD8+ T cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKCι-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3 and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.

The therapeutic landscape for relapsed or refractory large B-cell lymphoma (R/R LBCL) has undergone rapid and profound change, driven by cellular therapies, bispecific antibodies, and next-generation antibody-drug conjugates (ADCs). These advances have redefined historical standards while exposing persistent gaps in trial design, biological insight, and therapeutic sequencing. Recent randomized studies show that ADC- and bispecific-anchored regimens can outperform legacy chemotherapy comparators, yet interpretation is hindered by geographic heterogeneity, selective enrollment, and a proliferation of trials lacking contemporary control arms.Next-generation approaches including bispecific-ADC combinations, dual-target CAR-T constructs, and strategies explicitly designed to circumvent antigen escape are poised to challenge long-standing therapeutic hierarchies and may broaden curative potential to patients who are ineligible for, or relapse after, CAR-T. The field now stands at an inflection point where therapeutic innovation is advancing faster than the evidence infrastructure required to guide practice. Delivering durable, equitable benefit will require control arms aligned with current CAR-T standards, harmonized eligibility criteria, prospective molecular profiling, and adaptive trial platforms capable of evolving with the standard of care.As ADCs and bispecifics move earlier in treatment and diffuse into community practice, the central challenge is no longer the development of active therapies alone, but the creation of biologically rational, accessible, and interpretable pathways that make chemotherapy-free cure a realistic and universal goal for patients with R/R LBCL.

Modern intravenous (IV) iron formulations allow treatment of iron deficiency anemia (IDA) with one or two infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in the majority of patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining different effects on bone- and mineral-metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, which reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in over 20,000 patients from the TriNetX database, where FCM-treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited binding of dentin matrix protein 1 to [alpha]V[beta]3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast-growth factor-23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.

The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.

The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

The optimal graft-versus-host disease (GvHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains controversial. In this open-label, phase Ⅲ study, patients aged 14-70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose ATG (5 mg/kg)/PTCy (50 mg/kg), standard-dose ATG (total dose 10 mg/kg), or a PTCy (total dose 100 mg/kg)-based regimen for GvHD prophylaxis. The co-primary endpoints were the cumulative incidence (CI) of grade Ⅱ-Ⅳ acute GvHD (aGvHD) by day 100 and GvHD/relapse-free survival (GRFS) at 1 year post-transplant. A total of 407 patients were randomized to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GvHD prophylaxis. By day +100, the CI of grade Ⅱ-Ⅳ aGvHD did not differ significantly among the three groups (P=0.210). Although the overall incidence of chronic GvHD (cGvHD) was comparable across all groups (P=0.110), the 2-year CI of moderate-to-severe cGvHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups compared to the PTCy group (28.3%), without reaching statistical significance (P=0.095). No significant differences were observed in survival outcomes among the three groups. Notably, the cumulative incidence of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group compared to the other groups (P<0.001). This trial suggested that the three GvHD prophylaxis strategies presented similar efficacy in preventing grade II-IV aGvHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.

Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy afflicting 1 in 5000 individuals, is the second-most-common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the U.S. Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS; NCT06259292), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median (range) age of 53 (0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of post-menarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring intravenous iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). This data from CHORUS, the first national registry of its kind, provides reliable, real-world estimates of the incidence, prevalence and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of over two decades, during which substantial serious, preventable HHT morbidity, including early intracranial hemorrhage, may occur.