Haematologica

Mutational profiling in acute myeloid leukemia

Courtney D. DiNardo — 2026-05-01

Menin and BCL2 inhibitors – shaken and stirred

Alex Bataller — 2026-01-22

Silver bullets for the golden age: treating IDH-mutated acute myeloid leukemia in older patients

Ofir Wolach — 2025-12-11

ALX/FPR2 - the spleen’s cellular cleanup crew!

Sandeep K. Prabhu — 2025-10-16

Defying age: myth or reality?

Mary Eapen — 2025-10-16

Rethinking the effectiveness of hypomethylating agents in myelodysplastic syndromes: the 50%-2-year wall

Howard Oster — 2026-01-22

Transforming mantle cell lymphoma: the journey across eras

Mathias Castonguay — 2026-01-29

Interleukin-6 in Castleman disease subtypes: look to tissues, not just blood

Mariam Goubran — 2025-11-06

Introduction to the Review Series. Clonal hematopoiesis review series – from biology to clinical management

Anastasija A. Piric — 2026-05-01

Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies

J. Scott Beeler — 2026-02-05

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited genetic predisposition, and acquired conditions. Large-scale population and longitudinal sequencing studies have identified determinants of clonal behavior. Characterization of the natural history of CH has enabled the development of risk stratification models to identify individuals with CH at high risk of progression to MN, thereby providing a rationale for selecting patient populations best suited for therapeutic intervention trials. Emerging strategies include targeting mutation-specific vulnerabilities, modulating inflammatory pathways, reducing genotoxic therapy-induced clonal selection, and repurposing agents with efficacy in MN. In this review, we summarize current knowledge of the risk factors underlying CH development, highlight recent advances in understanding the determinants of clonal behavior including progression to MN, and discuss emerging therapeutic approaches for preventing malignant transformation and clinical trial design considerations.

What’s hidden in plain sight? Impact of clonal hematopoiesis on the risk and progression of nonhematologic cancers

José C. Martínez — 2025-09-04

Clonal hematopoiesis (CH) is a frequently observed phenomenon in aging individuals without apparent illness and exhibits an increased prevalence in cancer patients. Mechanistic studies indicate that mutant immune cells alter the tumor microenvironment, leading to increased inflammation, blood vessel formation, and immune cell exhaustion. Paradoxically, these changes also preserve stem-like T-cell pools that can be utilized by immunotherapy. CH may be incidentally detected in patients whose solid tumors are profiled by next-generation sequencing. Clinically, CH confers higher risks of therapy-related myeloid neoplasms, cardiovascular and inflammatory toxicities, and context-specific changes in treatment efficacy. Moreover, tumor-infiltrating CH independently shortens survival. Two validated risk scores can inform the risk for myeloid malignancy, yet surveillance, cardiometabolic management, and regimen selection still primarily rely on expert consensus. Because CH may be discovered incidentally, rigorous confirmation of variant origin when CH is suspected is essential to avoid misdirected therapy. We propose a pragmatic approach: (i) confirm CH with paired blood sequencing when feasible; (ii) integrate high-risk features into risk stratification, counseling, and monitoring for cytopenias and cardiovascular events; and (iii) prefer less genotoxic regimens when the oncologic benefit is comparable. Early trials blocking interleukin-1β suggest that targeting inflammation driven by CH may improve outcomes in patients with solid tumors. Prospective studies informed by mutation analysis and tracking clonal changes and inflammatory markers are needed to determine whether routine CH assessment can be integrated into precision oncology to improve outcomes for patients with solid tumors and CH.

Novel and emerging therapeutic strategies for clonal hematopoiesis

Mohsen Hosseini — 2025-11-13

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSC) acquire mutations that confer a competitive advantage over wild-type HSC, leading to their expansion in the bone marrow with clonal progeny that circulate in the blood and are most readily detected through peripheral blood sequencing. The prevalence of CH increases with age and is linked to a higher risk of hematologic malignancies and various non-malignant diseases, particularly atherosclerotic cardiovascular disease. CH is not merely a biomarker; it actively contributes to the pathogenesis of these age-related conditions. Therefore, targeting the expansion of mutant clones and their downstream effects offers an opportunity to prevent these adverse health outcomes. CH involves mutation-specific biological changes that sustain the abnormal HSC phenotype, including epigenetic dysregulation, aberrant inflammatory signaling, metabolic reprogramming, and altered intracellular signaling pathways. A deeper understanding of these processes has led to the development of targeted therapeutic approaches. This review addresses the practical challenges of implementing interventions against CH, focusing on balancing risk and benefit and selecting appropriate patients. It discusses emerging treatments targeting the pathogenic mechanisms in CH, such as epigenetic modulators, anti-inflammatory therapies, metabolic inhibitors, and signaling pathway inhibitors. We also highlight potential novel therapeutic strategies on the horizon, such as immune-based approaches for selective clonal elimination and gene-editing therapies to correct causative mutations. These advances reframe CH as a potentially modifiable condition rather than an inevitable consequence of aging, creating opportunities for early intervention before progression to overt disease.

Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny

Tal Bacharach — 2026-01-29

Clonal hematopoiesis is driven by the age-associated expansion of hematopoietic stem and progenitor cells that harbor somatic driver mutations; however, the mechanisms underlying the long-term persistence of these cells remain incompletely understood. This review frames clonal hematopoiesis through the lens of inclusive fitness, proposing that mutant pre-leukemic hematopoietic stem and progenitor cells enhance their evolutionary success not only through intrinsic self-renewal advantages, but also via indirect effects mediated by their differentiated progeny. We synthesize evidence showing that mutant immune cells promote inflammatory microenvironments that selectively impair wild-type hematopoietic stem cells while reinforcing mutant self-renewal, establishing self-sustaining feedback loops that shape clonal dynamics and systemic disease risk.

Clinical decisions in clonal hematopoiesis: a contemporary review for clinicians

Robert J. Vanner — 2026-02-05

Clonal hematopoiesis (CH) has emerged as a critical mediator of age-associated diseases, with far-reaching implications for hematologic malignancies, cardiovascular diseases, cancer therapy, autoimmune disorders, and other health conditions. This review synthesizes the current evidence supporting the integration of CH testing and monitoring into clinical practice, with a focus on translating scientific discoveries into actionable diagnostic and therapeutic strategies. We present a systematic framework for establishing and operating a dedicated CH program, drawing on institutional experience and evolving best practices. Our analysis encompasses risk stratification approaches, surveillance protocols, and intervention timing for various CH-associated conditions. Special attention is given to the challenges and opportunities in implementing CH screening within existing clinical workflows, including considerations regarding genetic counseling, interdisciplinary coordination, and patient education. By providing practical insights and evidence-based recommendations, this review aims to serve as a roadmap for healthcare institutions looking to develop comprehensive CH management programs that bridge the gap between molecular discoveries and clinical care delivery.

Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1

Valerio Ciaurro — 2025-11-06

Mixed-lineage leukemia (MLL) rearrangements (MLLr) and nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the anti-apoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLLr and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLLr, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS-1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, western blotting, and BH3 profiling. Treatment with DS-1594b and venetoclax exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the NPM1-mutated AML patient-derived xenograft model, DS-1594b single-agent treatment significantly extended survival. Importantly, compared with DS-1594b monotherapy, the combination of DS-1594b and venetoclax more profoundly reduced leukemic burden and prolonged mouse survival. Menin inhibition was the primary driver of transcription changes in this model and impacted the expression of anti-apoptotic regulators, providing a mechanistic explanation for the synergy observed between these drugs. Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.

IDH2 mutation is associated with favorable outcome among older adults with newly diagnosed acute myeloid leukemia treated with hypomethylating agent-based therapy

Fieke W. Hoff — 2025-11-06

Mutations of isocitrate dehydrogenase (IDH) are recurrent in newly diagnosed acute myeloid leukemia (AML) and their prevalence increases with age. The prognostic impact of IDH mutations in AML remains controversial. IDH inhibitors generally have a favorable side-effect profile, making them an attractive option for older patients. This retrospective analysis aimed to describe the prevalence and prognostic impact of IDH mutations in a large cohort of newly diagnosed AML patients aged ≥60 years enrolled in the Beat AML clinical trial. A total of 1,023 patients were included. IDH mutations were detected in 28% of patients, including 9.7% with IDH1mut, 18.9% with IDH2mut, and 1.0% with mutations in both IDH1 and IDH2. IDH mutations frequently co-occurred with DNMT3A (38%), NPM1 (35%), and SRSF2 (34%) mutations. In patients treated with intensive chemotherapy, IDH mutations were not prognostic for overall survival (OS) (P=0.76), while OS was longer for patients with IDH2mut compared to IDHwt in patients treated with hypomethylating agent (HMA)-based therapy (median OS, 18.5 vs. 10.2 months, P<0.001). IDH1 was not significant for outcome. IDH2 remained prognostic for OS after exclusion of patients receiving an IDH inhibitor (hazard ratio=0.60, 95% confidence interval: 0.41-0.89). Outcomes with TP53 or myelodysplasia-related gene mutations were also better with an IDH co-mutation (P=0.043, and P=0.006, respectively). In patients treated with HMA plus venetoclax (N=243), IDHmut was not prognostic (P=0.42). The high prevalence of IDHmut and favorable impact in patients treated with HMA-based therapy supports studies investigating the addition of targeted therapies to HMA-based regimens for older patients with IDH-mutant AML; mut: mutated; wt: wild-type.

Lipid dysregulation after hematopoietic stem cell transplant

Jane Koo — 2025-12-24

Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic hematopoietic stem cell transplant (allo-HSCT), primarily driven by endothelial injury and complement activation. Statins, combined with other drugs, are commonly used as prophylaxis against endothelial injury in some parts of the world but their mechanism of action has not been clearly defined. We hypothesized that dysregulation of lipids, or their precursors, ceramides, might be an important mechanism of endothelial injury, and that statins might ameliorate that dysfunction. We measured plasma ceramide species at baseline and day 14 in pediatric and young adult allo-HSCT recipients. Ceramide species in general were increased in those who later developed endothelial injury, manifest as TA-TMA. These findings highlighted ceramides as markers of endothelial stress, prompting us to explore whether statin prophylaxis could favorably modulate lipid and ceramide pathways. A single-arm phase I trial of pravastatin prophylaxis was also performed in patients at elevated risk of endothelial injury due to high body mass index to assess lipid and ceramide modulation over time. Multiple ceramide species were elevated in patients who developed TA-TMA and showed strong correlations with ST2 but not with sC5b-9. While ceramides were associated with TA-TMA in univariate models, only ST2 remained significant in multivariable analysis. Addition of ceramide levels to ST2 only modestly improved prediction of later TA-TMA in Receiver Operating Characteristic (ROC) analysis. Pravastatin prophylaxis was associated with distinct shifts in lipoprotein and ceramide profiles, potentially reflecting modulation of endothelial function. Pravastatin may alter ceramide and lipoprotein pathways in a clinically meaningful way, contributing to their role in endothelial protection.

Loss of endothelial miR-126 drives age-related decline in hematopoiesis

Dandan Zhao — 2025-12-04

Aging profoundly alters the bone marrow (BM) microenvironment and impairs hematopoietic stem cell (HSC) function. Here, we identify decrease of miR-126 derived from arteriolar endothelial cells (EC) as a key mechanism of impaired HSC self-renewal capacity during aging. In young BM, arteriolar EC express high levels of miR-126, which is transferred to HSC and supports these cells’ homeostasis and functional integrity. Using young and aged wild-type, endothelial-specific miR-126 knockout (EC-miR-126 KO), EC-Spred1 knockout (a functional model of EC-miR-126 upregulation), and EC/Sca-1 dual fluorescent reporter mice, we show that age-related increase in inflammatory cytokines (such as TNFα) reduces EC miR-126 expression and in turn drives loss of miR-126high CD31+Sca-1high EC-lined arterioles in the aging BM niche. Loss of arterioles in turn decreases the EC miR-126 supply to HSC, leading to expansion of HSC with limited self-renewal capacity. Remarkably, administration of a synthetic miR-126 mimic oligonucleotide restores EC-HSC communication and rescues aging-related HSC dysfunction. Our findings uncover a novel, non-cell-autonomous mechanism of HSC aging and highlight EC-derived miR-126 as a promising therapeutic target to rejuvenate hematopoiesis.

Age-related differences in donor selection priorities for allogeneic hematopoietic transplantation

Koji Kawamura — 2025-09-11

Patient age might influence donor selection priorities in allogeneic hematopoietic stem cell transplantation (allo-HCT), due to the differences in donor age, organ function, and resistance to graft-versus-host disease between younger and older patients. We compared the transplant outcomes between patients aged <50 years and those aged ≥50 years who received transplants from human leukocyte antigen (HLA)-matched related donors (M-RD, N=4,106), HLA one-antigen-mismatched related donors (1MM-RD, N=592), HLA two or three-antigen-mismatched related donors (23MM-RD, N=882), HLA-matched unrelated donors (M-UD, N=3,927), HLA one-locus-mismatched unrelated donors (1MM-UD, N=2,474), or unrelated cord blood units (U-CB, N=5,867). To assess the impact of donor age, the M-UD and 1MM-UD groups were further subclassified into younger (M-UD-Y, 1MM-UD-Y: donor age <50 years) and older (M-UD-O, 1MM-UD-O: donor age ≥50 years) donor subgroups. Among patients aged ≥50 years, overall survival in the M-UD-Y group was significantly superior to that in the M-RD group (hazard ratio=0.87, P=0.0039), whereas the M-UD-O group showed no advantage (hazard ratio=1.08, P=0.48). In this age group, 1MM-RD, 23MM-RD, and U-CB were associated with significantly inferior overall survival, while neither 1MM-UD-Y nor 1MM-UD-O was. NRM was significantly lower in the M-UD-Y group than in the M-UD-O group among patients aged ≥50 years, without increasing relapse risk. For patients aged <50 years, overall survival in the M-UD-Y and M-UD-O groups was comparable to that in the M-RD group, but 23MM-RD, 1MM-UD-Y, and U-CB were associated with inferior overall survival. Therefore, donor selection priorities in allo-HCT might differ according to recipient age. A younger M-UD might be preferred for patients aged ≥50 years.

Neurodegenerative Langerhans cell histiocytosis: long-term follow-up of 63 patients from the Italian Registry

Irene Trambusti — 2025-11-27

Neurodegenerative Langerhans cell histiocytosis (ND-LCH) is a potentially devastating complication of LCH. We analyzed the natural history and the long-term outcome of patients with ND-LCH enrolled in the Italian LCH registry. ND-LCH was diagnosed in 63 of 637 patients with LCH (10%). Overall, at ND-LCH diagnosis 60% (38/63) patients were asymptomatic, 24% (15/63) had mild clinical manifestations including abnormal neurological examination and/or evoked potentials, and 16% (10/63) had overt symptoms. Brain magnetic resonance imaging (MRI) showed progressive structural changes in 13 of 63 (21%) patients over a median time of 1.5 years. Clinical ND-LCH developed after a median of 2.5 years since ND-LCH diagnosis. Thirty of 63 patients (17 pauci-symptomatic, 11 symptomatic, two asymptomatic but with severe brain MRI) received treatment, and 17 of 30 (57%) were stable or improved at the last follow-up). Thirty-three of 63 patients (mostly asymptomatic) were not treated and 31 of 33 (94%) remained stable through follow-up. At univariable analysis, the risk of developing overt clinical symptoms increased with LCH reactivations (odds ratio [OR]=6.40; P=0.018), severe brain MRI abnormalities at ND-LCH diagnosis (OR=10.40; P<0.001), and MRI findings worsening during follow-up (OR=10.25; P=0.001). The association of overt neurodegeneration with reactivations and MRI findings worsening was confirmed at multivariable analysis (OR=8.15; P=0.040; and OR=7.31; P=0.034, respectively). In conclusion, asymptomatic patients presenting with mild radioneuroimaging lesions at ND-LCH onset remained stable during follow-up; conversely, a history of LCH reactivation and worsening of brain MRI findings were associated with the appearance of overt clinical symptoms. These results may lay the basis for patients selection for treatment and different monitoring strategies.

Decitabine plus all-trans retinoic acid versus decitabine monotherapy for myelodysplastic syndromes with excess blasts: a multicenter, randomized controlled trial

Xinping Zhou — 2025-11-20

Despite standard treatment with hypomethylating agents, the prognosis of patients with higher-risk myelodysplastic syndrome (MDS) remains poor. All-trans retinoic acid (ATRA) has demonstrated promising efficacy in unfit patients with acute myeloid leukemia. This multicenter controlled trial randomized (1:1) untreated patients with MDS with excess blasts (MDSEB) to ATRA plus decitabine (ATRA at 25 mg/m2/day in 2 divided daily doses throughout the 28-day cycle plus decitabine at 20 mg/m2 on days 1-5) or decitabine alone (20 mg/m2 on days 1-5). The primary endpoint was the overall response rate within four treatment cycles. A total of 227 patients were randomized. Four patients who did not commence therapy were excluded from the modified intention-to-treat (mITT) analysis. The median patient age was 62 years (range, 19-81). The overall response rate was 78% (86/110) in the ATRA group versus 51% (58/113) in the decitabine group (odds ratio =3.40; 95% confidence interval [CI]: 1.90-6.09; P<0.001). The ATRA group also had a higher complete remission rate (23% vs. 12%; odds ratio =2.05; 95% CI: 1.02-4.25; P=0.042). With a median follow-up of 30.1 months, progression-free survival (PFS) was 14.9 months in the ATRA group versus 10.5 months in the decitabine group (hazard ratio [HR]=0.70; 95% CI: 0.51-0.97; P=0.03). The overall survival was 23.0 months and 19.3 months, respectively (HR=0.77; 95% CI: 0.54-1.09; P=0.137). The two groups did not differ in grade 3 or higher hematological adverse events. In conclusion, adding ATRA to decitabine increased the overall response rate and prolonged PFS in adult patients with MDS-EB without increasing hematological toxicity. This study was registered at Chinese Clinical Trial Registry (www.chictr.org.cn, identifier: ChiCTR1800018307).

Marked survival gains in patients ≤ 65 years with advanced-stage mantle cell lymphoma: a pooled analysis of six randomized phase III trials, 1996-2020

Linmiao Jiang — 2025-10-30

Mantle cell lymphoma (MCL) remains a challenging and generally incurable disease. We aimed to evaluate survival trends in advanced-stage MCL over the past three decades, focusing on the impact of evolving first-line therapies. We pooled six randomized phase III trials of treatment-naïve, advanced-stage MCL patients enrolled between 1996 and 2020. Patients were grouped into four eras by enrollment period. Failure-free survival (FFS) and overall survival (OS) were compared across eras using Kaplan-Meier methods and Cox regression adjusted for the Mantle Cell Lymphoma International Prognostic Index (MIPI) and treatment. Dynamic survival trends were analyzed using penalized splines. Among 2,541 MCL patients, survival outcomes have improved steadily since 1996. In younger and transplant-eligible patients (≤ 65 years), there was a strong increase in median OS from 4.9 years (5-year OS: 49%) in the period 1996-2000 to 13.8 years (73%) in 2004-2014 and was not reached (84%) in 2016-2020. In older and transplant-ineligible patients, median OS improved from 3.8 to 4.8 years (5-year OS: 40-49%) between 1996 and 2014. Dynamic trends revealed a sharp decline in treatment failure and mortality risk between 2000 and 2005, followed by sustained improvements. Patients receiving the same treatment regimens had comparable FFS and OS across eras. Adjusting for treatment eliminated most survival trends, underscoring the impact of rituximab, ASCT, high-dose cytarabine, and ibrutinib on survival improvements. In conclusion, OS in MCL has substantially improved over the past three decades, especially in younger patients, driven largely by improvements in first-line treatment. In older patients, despite significantly improved OS in recent decades, there remains an urgent need for further improvements.

Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease

Asami Nishikori — 2025-09-11

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. Two major clinical subtypes, idiopathic plasmacytic lymphadenopathy (iMCD-IPL) and iMCD with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (iMCD-TAFRO), have distinct pathophysiological mechanisms. While interleukin-6 (IL-6) is known to be elevated in iMCD, differences in the sources of IL-6 production between subtypes remain unclear. We examined the source of IL-6 production and its transcriptional regulation across iMCD subtypes using immunohistochemistry, in situ hybridization, and gene expression profiling. Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO. Plasma cells exhibited stronger IL-6 protein expression in iMCD-IPL than in iMCD-TAFRO. Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation. Our findings suggest that XBP1-mediated IL-6 production may contribute to the pathogenesis of iMCD-IPL, potentially explaining its favorable responses to IL-6 blockade therapy. In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype. Future studies should clarify how proteomics and gene expression profiling could inform subtype-specific therapeutic strategies in iMCD.

Ethnicity affects relapse-free survival in immunemediated thrombotic thrombocytopenic purpura

Júlia Weisinger — 2026-01-08

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by a severe, antibody-mediated deficiency of ADAMTS13 activity. The B-cell depleting agent rituximab is effective in restoring ADAMTS13 activity and therefore preventing relapses. However, the risk of relapse appears heterogeneous among patients, although the underlying causes are elusive. Preliminary reports suggested that African ancestry could be associated with decreased relapse-free survival (RFS). Data from the registry of the French National Thrombotic Microangiopathy Reference Center were used to further address the role of ethnicity on response and RFS after rituximab administration in the acute as well as in the preemptive setting. A total of 790 patients (134 patients of African ancestry and 656 patients of European ancestry) were included in the study. Time from rituximab administration to ADAMTS13 recovery was comparable between the two cohorts. Patients of African ancestry had inferior 3-year RFS after the first rituximab-treated episode compared to patients of European ancestry (P<0.05). In multivariate analyses, African ancestry was identified as an independent risk factor for relapse (hazard ratio [HR]=1.36; P<0.05), as well as male sex (HR=1.21; P<0.05) and type of index episode treated by rituximab (relapsed disease vs. initial episode, HR=1.62; P<0.05). Moreover, time to relapse shortened progressively after consecutive courses of rituximab, regardless of ethnicity (P<0.05). These results indicate that ethnicity affects RFS with patients of African ancestry relapsing earlier, suggesting that a closer ADAMTS13 monitoring might be necessary in high-risk patients.

Differentiating pathogenic from bystander autoantibodies in immune thrombocytopenia using intact glycoproteindeficient megakaryocytes

Nanyan Zhang — 2025-12-11

Autoantibodies targeting platelet surface glycoproteins (GP) are the primary cause of immune thrombocytopenia (ITP), however testing for these autoantibodies is not routinely employed mainly because current diagnostic tests lack sufficient sensitivity. To overcome this and other diagnostic limitations, we generated HLA class I-negative, blood group O, induced pluripotent stem cell lines, and gene-edited them to produce a novel panel of GP-deficient, in vitro-derived megakaryocytes (MK). Using GPIIb-, GPIbα- and GPIX-deficient MK allowed sensitive and specific identification and characterization of both GPIIb-IIIa- and GPIb/IX-specific plasma autoantibodies, as well as rare, previously undescribed patient autoantibodies targeting GPIX. The availability of frozen bioengineered MK expressing select platelet GP antigens on their surface simplifies the detection of anti-platelet autoantibodies involved in disease progression, while avoiding detection of non-pathogenic bystander autoantibodies that are sometimes generated by secondary exposure to “cryptic epitopes”, and that can otherwise confound diagnosis and treatment. Use of intact MK selectively deficient in the GP that comprise the major targets of platelet autoantibodies has the potential to significantly improve clinical diagnosis and treatment of ITP.

CSF1R modulates megakaryopoiesis by targeting RUNX1 in immune thrombocytopenia

Haohao Han — 2025-12-18

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by platelet destruction and defective megakaryopoiesis. However, the mechanisms underlying megakaryocyte (MK) dysfunction in ITP remain unclear. To address this, we performed single-cell RNA sequencing (scRNA-seq) on bone marrow cells from a newly diagnosed ITP patient. ScRNA-seq analysis revealed a marked upregulation of colony-stimulating factor 1 receptor (CSF1R) in MK compared with healthy control. This finding was independently validated by flow cytometry in additional clinical samples. In vitro, MK differentiation and maturation were significantly impaired in ITP, and these defects were rescued by inhibition of CSF1R. In an active murine model of ITP, CSF1R inhibition accelerated platelet recovery. Mechanistically, elevated CSF1R expression suppressed the transcription factor RUNX1, a key regulator of megakaryopoiesis. In conclusion, our findings identify CSF1R as a previously unrecognized regulator of megakaryopoiesis and suggest it represents a promising therapeutic target in ITP.

COUP-TFII regulates hemoglobin switching by activating the BCL11A-XL repressor LIN28B and directly binding δ and β globin promoters in fetal versus adult erythroid cells

Carlotta Frigo — 2025-11-27

The reactivation of fetal globin genes is the most promising treatment for β-hemoglobinopathies. This implies the reversal of the naturally occurring hemoglobin switching. Here, we show that expression of the orphan nuclear receptor COUP-TFII in adult HUDEP2 erythroid precursor cells activates γ-globin (HbF) at the expense of β-adult globin by specific occupation of the ‘adult’ δ-β-region within the β-locus. Notably, although COUP-TFII and the main γ-globin repressor BCL11A-XL share a similar DNA binding consensus and a large number of chromatin targets, including the locus control region of the β-locus itself, they bind differentially to the γ and β promoters, eliciting an opposite transcriptional outcome. In addition, we find that COUP-TFII activates Lin28B, a known post-transcriptional repressor of BCL11A-XL. Our work identifies a molecular mechanism that could be leveraged to increase γ-globin levels in patients affected by β-hemoglobinopathies.

Splenic erythrophagocytosis is regulated by ALX/FPR2 signaling

Haley Asplund — 2025-09-11

Maintaining a healthy pool of circulating red blood cells (RBC) is essential for adequate perfusion, as even minor changes in the population can impair oxygen delivery, resulting in serious health complications including tissue ischemia and organ dysfunction. This responsibility largely falls to specialized macrophages in the spleen, known as red pulp macrophages, which efficiently take up and recycle damaged RBC. However, questions remain regarding how these macrophages are acutely activated to accommodate increased demand. Proresolving lipid mediators stimulate macrophage phagocytosis and efferocytosis but their role in erythrophagocytosis has only recently been described. To investigate the role of lipid mediators in red pulp macrophage function, we targeted the ALX/FPR2 signaling pathway, as this receptor binds multiple lipid mediator ligands eliciting potent macrophage responses. We found that mice with Fpr2 deletion exhibited disrupted erythrocyte homeostasis resulting in an aged RBC pool, decreased markers of splenic RBC turnover, and altered splenic macrophage phenotype characterized by changes in heme metabolism. Upon activation of on-demand erythrophagocytosis, production of the ALX/FPR2 ligand, lipoxin A4 (LXA4), was induced in the spleen while receptor-deficient animals were unable to efficiently clear damaged RBC, a defect that was conserved in mice with myeloid-specific FPR2 deletion. Similarly, mice lacking the LXA4 biosynthetic enzyme displayed defective erythrophagocytosis that was rescued with LXA4 administration. These results indicate that the ALX/FPR2 signaling axis is necessary for maintenance of RBC homeostasis and that LXA4 activation is a critical aspect of the red pulp macrophage response to acute erythroid stress.

CPX-351 in secondary/high-risk acute myeloid leukemia: a meta-analysis of randomized and real-world studies encompassing more than 3,200 patients

Matteo Molica — 2025-12-11

Carbon footprint of direct oral anticoagulants in atrial fibrillation and venous thromboembolism

Laurence Chery — 2025-12-11

Cell-free BRAF^V600E levels predict progression-free survival in children with Langerhans cell histiocytosis treated with dabrafenib and maintenance chemotherapy

Lei Cui — 2025-11-27

Rituximab, dexamethasone, etoposide, ifosfamide and carboplatin (R-DeVIC) in relapsed or refractory central nervous system lymphoma: a retrospective multicentre clinical study

Kudret Kama — 2025-12-11

Integrative clinical and molecular characterization of an acute promyelocytic leukemia-like subgroup with high early death risk in newly diagnosed acute myeloid leukemia: a multicenter study

Mingkai Shu — 2025-11-27

Loss of nuclear myosin 1 causes hemostatic defects and immune dysregulation

Tomas Venit — 2025-11-20

Single-cell profiling of CD19-directed CAR T-cell phenotypes and immune system dynamics in pediatric B-cell acute lymphoblastic leukemia

Aleksandra Oszer — 2025-11-20

Altered glycosylation profile of anti-HPA-1a-specific antibodies: insights from a prospective fetal and neonatal alloimmune thrombocytopenia cohort

Janita J. Oosterhoff — 2025-12-04

Severe allergic and anaphylactic transfusion reactions in consecutive recipients from the same donor

Patrick Terrence Brooks — 2025-11-27

Genetic alterations of SENP6 in multiple myeloma disrupt genome and proteome stability, sensitizing to proteasome inhibition

Frederik Herzberg — 2025-12-04

Allopurinol increases DNA-thioguanine nucleotides during maintenance therapy in pediatric acute lymphoblastic leukemia

Jonatan Källström — 2025-12-04

Comparative effectiveness of immunotherapy alone or with chemotherapy as first-line treatment for marginal zone lymphoma

Adam J. Olszewski — 2025-11-27

Inherited DNA repair variants are associated with clonal hematopoiesis and cardiovascular risk in men with metastatic prostate cancer

Olisaemeka Ogbue — 2025-12-04

Multi-omics analysis reveals a unique epigenetic signature in MYD88 wild-type Waldenström macroglobulinemia

Karan Chohan — 2025-12-04

Myeloproliferative neoplasms with clinically relevant paroxysmal nocturnal hemoglobinuria: clinical correlations and outcomes

Priyansh Faldu — 2025-11-27

Rapid and accurate identification of acute promyelocytic leukemia with a novel multiparametric flow cytometric scoring system

Alessandro Laganà — 2025-12-04

Unemployment in patients with histiocytic neoplasms is frequent and associated with clinical and treatment characteristics

Anne S. Reiner — 2025-12-04

Functional impact of a deep intronic variant in the RPS19 gene detected in a case of Diamond-Blackfan anemia syndrome

Rika Kanezaki — 2026-01-22

t(11;14) multiple myeloma patient: minimal residual disease after 10 years of follow-up - a case report

Sarah Decheiver — 2025-12-24

Common ancestral origin of indeterminate dendritic cell tumor and chronic myelomonocytic leukemia in clonal hematopoiesis

Aki Sato — 2026-01-15

Is Bruton tyrosine kinase a potential target to treat mast cell neoplasms? Systemic mastocytosis associated with chronic lymphoid leukemia successfully treated with acalabrutinib monotherapy: a case report and review of the literature

Manlio Fazio — 2025-12-11

A novel GATA1 variant linking germline and somatic myelodysplastic syndrome in two patients

Nuria Revilla — 2025-12-24

Peripheral T-cell lymphoma in adult-onset familial hemophagocytic lymphohistiocytosis type 2 and heterozygous LRBA mutation

Marco Tembrink — 2026-03-19

Genetic testing guides therapy in children with refractory cytopenias

Yael Gernez — 2026-01-08