Targeting mitochondrial oxidative phosphorylation (OXPHOS) enhances the effects of standard chemotherapy and overcomes treatment resistance in pre-clinical models of acute myeloid leukaemia (AML). So far, the few clinically available OXPHOS inhibitors have shown adverse effects or limited potency in clinical trials, therefore, identification of safe and effective drugs that can target mitochondrial metabolism in AML is critical. Here, we performed a high-throughput drug-repurposing screen, designed to identify clinically applicable OXPHOS-specific inhibitors through nutrient sensing. We uncover itraconazole, an FDA-approved antifungal compound, as a potent OXPHOS inhibitor in AML cells. Mechanistically, through stable isotope-assisted metabolomics and functional studies, we reveal that CYP51A1, which is part of the cytochrome P450 family and the prime target of azole antifungals, is involved in mitochondrial respiration and ETC complex I activity in AML cells. Critically, we demonstrate that itraconazole and related azole antifungals interfere with tricarboxylic acid cycle activity and inhibit OXPHOS through the inhibition of electron transport chain complex I activity. Over-expression of yeast NADH dehydrogenase-1 (NDI1) restored mitochondrial NADH oxidation and complex I activity upon itraconazole treatment. Using patient-derived cells and pre-clinical xenograft models, we demonstrate that itraconazole targets therapy-resistant leukaemic stem cells (LSCs) when used in combination with cytarabine, highlighting the repurposing potential for itraconazole as a clinically safe and effective therapeutic option for AML LSC eradication.

Menin inhibitors (MI) disrupt the binding of Menin to MLL1 leading to repression of MLL1 or MLL1-fusion protein (FP) target genes, including reduced levels of HOXA9 and MEIS1 in AML with mutant (mt) NPM1 or MLL1-rearrangement (r). While MIs are relatively well-tolerated and induce clinical remissions, these are often short-lived due to development of resistance followed by AML relapse. Through repeated shocks with the MI SNDX-50469, a precursor tool compound to revumenib, followed by recovery, we developed MI-resistant (MITR) AML MV4-11 and OCI-AML3 cells. Present studies show that, compared to MI-sensitive parental cells, MITR cells exhibit an altered epigenome, transcriptome and proteome, without Menin mutations. Through a CRISPR screen, novel druggable MI co-enrichments were identified and targeted, including BRD4, SMARCA4, and CREBBP. Co-treatment with the MI and the SMARCA4/SMARCA2 (BRG1/BRM) inhibitor FHD-286 or the BET proteins inhibitor OTX015 (birabresib), synergistically induced in vitro lethality in MITR and MI-resistant AML cells expressing the mutant Menin (M327I), as well as in patient-derived (PD) AML cells with MLL1-r or mtNPM1 that exhibited ex vivo resistance to MI. Compared to each drug alone, co-treatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1.

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated curative potential in B cell malignancies, yet translating this success to chronic infections like human immunodeficiency virus (HIV) remains a major challenge. In people living with HIV (PLWH) on suppressive antiretroviral therapy (ART), low antigen levels limit CAR-T cell expansion and persistence. We previously reported data from a pilot study which suggested that HIV-targeted CD4CAR-T cells could overcome this barrier through exogenous antigen supplementation, leading to robust in vivo expansion. Here, we sought to comprehensively confirm and expand on those findings. We tested a broad array of strategies to enhance CD4CAR-T cell efficacy, including CRISPR-Cas9-mediated gene editing of immune checkpoint and HIV-associated genes, single and pooled competitive infusions of engineered CAR-T cells, distinct CAR constructs incorporating either CD28 or 4-1BB costimulatory domains, and exogenous antigen boosting. We also developed highly sensitive droplet digital PCR (ddPCR) assays both to quantify CAR-T cell frequency and corroborate flow cytometry-based quantification of CD4CAR T-cell expansion. We evaluated these new approaches across multiple NHP models of HIV, including both simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected, ART-suppressed NHPs. Although CD4CAR-T cell products exhibited antigen-specific proliferation and cytotoxicity ex vivo, they failed to expand, persist, or control viremia in vivo. We were also unable to confirm previously observed CD4CAR T cell expansions from our earlier studies, which will be retracted. Together these data highlight the need for alternative strategies to potentiate anti-HIV CD4CAR-T cells in the immunocompetent setting.

Plasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P. knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Like its close relative Plasmodium vivax, P. knowlesi relies on Duffy-Antigen Receptor for Chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we reveal that P. knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate in Duffy-negative (Fy-) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy-erythrocytes and to resist inhibition by a-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbpα and dbpγ genes, resulting in a new chimeric gene dbpαγ. Using CRISPR-Cas9 targeted reversion, we were able to demonstrate that dbpαγ is essential for invasion of Fy- erythrocytes. These findings shed new light on the invasion plasticity of P. knowlesi, with implications for its potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P. vivax.

In this retrospective analysis of 584 patients who received CAR T-cell therapy for LBCL at six Australian centres we found no association between time of infusion and outcome, accounting for confounders, suggesting minimal clinical impact of chronobiology in this setting.

To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can be caused by maternal IgG alloantibodies against the human platelet antigen 1a (HPA-1a), a Leu33Pro polymorphism at the PSI domain of the β3 subunit shared by integrins αIIbβ3 and αVβ3. Although serologic detection of anti-HPA-1a alloantibodies has long aided FNAIT diagnosis, the disease remains a major clinical challenge due to unpredictable severe outcomes, particularly intracranial hemorrhage and fetal loss. To define the molecular basis of HPA-1a immunogenicity and antibody pathogenicity, we determined crystal structures of the HPA-1a antigen bound to Fabs from four anti-HPA-1a monoclonal antibodies, including three clinically relevant maternal alloantibodies (26.4, D-204, and M-204) and one murine antibody (SZ21). The structures reveal that all antibodies recognize an HPA-1a epitope centered on Leu33, spanning both PSI and I-EGF1 domains of β3 integrin. Variations in antibody binding interfaces account for differential affinities to both αIIbβ3 and αVβ3, while distinct binding orientations determine whether antibody engagement stabilizes the bent inactive β3 conformation. Functional assays demonstrated antibody-dependent inhibition of αIIbβ3-mediated platelet aggregation, thrombus formation, and clot retraction, as well as αVβ3-mediated endothelial adhesion and spreading. These results establish the structural framework of HPA-1a alloantigenicity, explain the conformational selectivity of anti-HPA-1a antibodies, and elucidate how they block integrin activation. The findings provide mechanistic insight into FNAIT pathogenesis and suggest that antibody heterogeneity in affinity and function may contribute to clinical variability. Furthermore, these findings demonstrate antibody-mediated stabilization of the PSI/I-EGF1 domain as a potential strategy for allosteric modulation of integrin structure and function.

Hematopoietic stem cell (HSC) transplantation is a life-saving therapy for immune deficiencies and hematologic malignancies, but its efficacy is limited by poor engraftment. Therapeutic enhancement of HSC grafts requires deeper insight into the intrinsic determinants of their regenerative capacity. Here, we identify mechanical robustness as a critical feature distinguishing human HSCs from multipotent progenitors (MPPs). Through integrative biomechanical and transcriptomic profiling, we show that ZNF467 is a key regulator of HSC mechanical integrity. Loss of ZNF467 disrupts HSC mechanical fitness and abolishes long-term engraftment. Conversely, an engineered phase-separating ZNF467 variant enhanced mechanical strength and engraftment by activating a mechanoresponsive transcriptional program, including upregulation of ICAM1. ICAM1+ HSPCs exhibit superior biomechanical properties and improved engraftment efficiency. Furthermore, phase separation activity of nucleoplasmic ZNF467 (npZNF467) is crucial for its mechanical reprogramming function, and ectopic npZNF467 expression enhances the engraftment capacity of MPPs. Our findings establish biomechanical regulation as an important determinant of stem cell identity and reveal new strategies for engineering stem cells with enhanced regenerative capacity.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening condition. Caplacizumab substantially shortens the time to clinical response, yet delayed platelet count recovery is occasionally observed, raising concerns about iTTP refractoriness. This retrospective multicenter study analyzed 204 acute iTTP episodes reported to the German REACT-2020 and Austrian ATMAR registries, all treated with caplacizumab. Refractoriness was assessed using the 2017 International Working Group criteria and the more stringent definition by the French Reference Center for Thrombotic Microangiopathies. We evaluated time to platelet recovery and presence of confounding clinical conditions, potentially accounting for persistent thrombocytopenia, in all episodes. By day 5 after caplacizumab initiation, 83.8% of patients (171/204) achieved a clinical response, and the remaining 16.2% (33/204) showed at least a doubling of the platelet count. Only three patients (1.5%) met laboratory criteria for refractoriness. In all cases, plausible alternative causes were present (e.g., missed doses, infection). No patient was refractory without a confounding factor. In 8/204 patients (3.9%) we observed a markedly prolonged thrombocytopenia (≥10 days) and identified confounding conditions in all cases. In the stratified Cox model, the presence of alternative causes of thrombocytopenia was the only independent determinant of delayed platelet count normalization (HR 0.16, 95% CI 0.09-0.28, p < 0.001), whereas baseline parameters were not predictive. In the context of caplacizumab-based therapy, true refractoriness is rare. Delayed platelet count recovery is predominantly attributable to concomitant clinical conditions. Careful clinical assessment and context-sensitive interpretation of treatment response before escalating iTTP-specific therapy may avoid unnecessary treatment intensification and associated risks.

Acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is a primary cause of early transplant mortality after bone marrow transplantation (BMT), driven by local antigen presentation and T-cell expansion. We sought to clarify the role of various donor dendritic cell (DC) subsets in this process in order to define therapeutic strategies to prevent gut GVHD. Donor plasmacytoid DC (pDC) were prominent in the ileum of BMT recipients without GVHD but were largely absent in gut during GVHD. In contrast, donor XCR1+ conventional DC (cDC) were dramatically increased in the mesenteric lymph nodes (mLN) of BMT recipients with GVHD. We utilized Xcr1-DTR mice and Clec4c-DTR mice to enable highly efficient XCR1+ cDC versus pDC depletion. Donor XCR1+ cDC but not pDC deletion attenuated lethal GVHD, depleting most cDC presenting alloantigen, which inhibited α4β7 and the expansion of alloantigen-specific donor Th1 cells in the gut. Aldehyde dehydrogenase 1A (ALDH1A) expression by cDC is known to modulate GVHD and we thus examined the effect of a pan-ALDH1 inhibitor, WIN18,446, on this axis. WIN18,446 administration improved survival and these effects were ALDH1A1-specific but mediated by inhibition of CD11b+ rather than XCR1+ cDC, inhibiting alloantigen-specific Th17 cell differentiation in the gut. These findings highlight the limited role of pDC in the induction of gut GVHD and identify differential and dominant roles for XCR1+ and CD11b+ donor cDC in controlling Th1 and Th17 mediated gut aGVHD. The targeting of donor cDC subsets represents an effective strategy to prevent lethal gut GVHD.

The Phase 1/2 Intergroup study E4412 (NCT01896999; ClinicalTrials.gov) investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) in relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) while concurrently targeting CD30+ Hodgkin Reed Sternberg cells with the antibody-drug conjugate brentuximab vedotin (BV). 147 patients ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients are included in primary efficacy analysis. The primary endpoint, complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (one-sided p=0.29). The median survival follow-up is 38.0 months (interquartile range 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the two arms (HR=0.78, CI 0.39-1.57, one-sided p=0.24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, was similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared to BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned post-hoc comparison; 58 patients received SCT; 36-month PFS (from SCT) was greater than 90% for both arms. Sixty-six patients were alive and progression free after the first scan (disease evaluation) and did not undergo SCT. The 36-month PFS (from first scan) was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared to 45.8% (26.3, 63.4) for BV/Nivo (HR=0.45, CI 0.19-1.08, one-sided p=0.03). The study did not meet its primary endpoint of superior CR rate for the triplet, but it supports the use of checkpoint-ADC induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT for the triplet of BV/Ipi/Nivo.

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor (ct)DNA sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling timepoints, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista - a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma - to samples obtained from the GHSG HD21 trial following two cycles of treatment (MRD-2) using a case-cohort-design. Patients with positive MRD-2 were at higher risk for relapse, progression or death compared with MRD-2 negative patients (4-year progression-free survival (PFS): 36.7% vs. 82.2%; HR 5.3, 95%CI 2.0-13.8; p = 0.0008). Following inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 had 4-year PFS rates of 72.2% vs. 95.3%. By combining MRD-2 with PET-2, patients were stratified into three distinct groups regarding risk of relapse: low (MRD-2 negative and PET-2 negative), intermediate (MRD-2 positive or PET-2 positive), and high (MRD-2 positive and PET-2 positive). In summary, these results suggest that assessment of MRD-2 by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homologue transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cremice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by "liberated" Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice, despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, HampmRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that "liberated" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and that Tfr2 and Hfe exhibit non-redundant functions under chronic iron loading, but act cooperatively to induce hepcidin in response to an acute iron challenge.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk, single cell (sc) TCR, and scRNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T-cells. We identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN- and RNA-seq that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in HDACi-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely utilized for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

NXT007 is a next-generation, activated factor VIII (FVIIIa)-mimetic bispecific antibody under investigation in the phase 1/2 NXTAGE trial (jRCT2080224835). Here, we report the primary analysis of the multiple-ascending-dose Part B in people with hemophilia A (PwHA). Eligible participants were men with severe HA without FVIII inhibitors. Four dose cohorts (B1-B4) were planned, with NXT007 administered subcutaneously at maintenance doses of 0.072 mg/kg, 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. Primary endpoints were safety (adverse events [AEs] and serious AEs [SAEs]), tolerability, pharmacokinetics, pharmacodynamics, and efficacy; secondary endpoints included incidence of anti-NXT007 antibodies (ADAs). Participants in cohorts B1 (n=10), B2 (n=6), B3 (n=6), and B4 (n=8) had received NXT007 for a median (minimum-maximum) of 114.1 (29-140), 96.4 (88-112), 58.1 (52-72), and 22.2 (4-28) weeks, respectively. Two participants discontinued treatment: NXT007-unrelated AE (n=1) and complete loss of NXT007 exposure due to ADAs (n=1). Participants' plasma NXT007 concentration showed a dose-dependent increase, and predicted FVIII-equivalent activity reached a non-hemophilic level (≥40 IU/dL) in B2 onwards. NXT007 had a favorable safety profile at all doses. Most AEs were mild/moderate and all three SAEs were considered unrelated to NXT007. Mean annualized treated bleed rates were 1.48 (B1), 0.28 (B2), 0.00 (B3), and 0.00 (B4). Pharmacokinetics-affecting NXT007 ADAs were observed in two participants, including the participant in B1 who discontinued. NXTAGE Part B demonstrates that NXT007 could provide non-hemophilic coagulation activity in PwHA, with a less burdensome dose regimen than currently available therapies.

In a real-world analysis of brexucabtagene autoleucel (brexu-cel) recipients with relapsed/refractory B-ALL (n = 278), lack of response to prior blinatumomab correlates with significantly worse post CAR-T outcomes.

VCAR33, a donor-derived CD33-directed chimeric antigen receptor (CAR) T cell product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe pre-clinical characterization of the VCAR33 construct, which was optimized for long-term anti-tumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in Arm A (bone marrow blasts ≥ 5%) at dose level 1 (DL1; 1 x 106 CAR+ T cells/kg) and 8 patients in Arm B (bone marrow blasts < 5%) at DL1 (n=5) and DL2 (3 x 106 CAR+ T cells/kg; n=3). The study ended for non-safety reasons before escalation to DL3 (1 x 107 CAR+ T cells/kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all < grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 ≥ grade 3) and 1 patient (6.7%) had grade III acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in Arm A and 1 Arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary anti-leukemic activity. ClinicalTrials.gov: NCT05984199.

Immune thrombocytopenia (ITP) is associated with a variable and unpredictable clinical course in children, including a spectrum of bleeding and systemic symptoms in the months following diagnosis. Although many children will have spontaneous resolution of disease prior to 1 year, up to 30% will go on to develop chronic disease. Known predictors for developing chronic ITP are limited, making clinical management and guidance during this early course of disease very challenging. Additionally, the pathophysiology of immune dysregulation in ITP is complex, with multiple variables likely contributing to the development of chronic disease. We aimed to create a statistical model to predict development of chronic ITP. Utilizing a retrospective training cohort of 611 children with ITP from two institutions and two validation cohorts comprised of 161 children, we developed and validated a multivariable logistic regression model and found that age, sex, IgG, IgA, IgM, presenting platelet count, presenting lymphocyte count, known secondary cause at diagnosis, and DAT positivity were useful in predicting chronic ITP. The external validations demonstrated consistent discriminative performance and clinical utility. The model is available for use at https://opal.shinyapps.io/citp-rm/. A chronicity prediction tool to use at the time of ITP diagnosis will better equip hematologists to counsel patients and families and engage in appropriate treatment strategies for individual patients earlier in their course.

We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with siRNA, delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially impacting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies.

Caring for individuals with hematological disorders is increasingly complex, and with medical complexity often comes ethical complexity. Prognostic uncertainty, stakeholder conflicts, and myriad other ethical challenges often contribute to situations that can benefit from ethics support. Through the presentation of three vignettes focusing on ethical dilemmas arising from hematology cases, we review the four phases of clinical ethics consultation: consult triage; ethics consult intake; stakeholder meeting(s) and additional data collection; and ethics analysis and recommendations. In tandem, we review some of the most common ethical framework/approaches used to inform hematology ethics consultation support services. We conclude that ethics consult services can be a valuable resource in providing care for patients with blood disorders and are a vital resource to enhance patient care, support clinicians, and ensure that difficult choices are navigated with clarity, compassion, and integrity.