bims-tremyl 2026-07-19 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–07–19
28 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Subclonal MECOM rearrangements in myeloid neoplasms: enriched for TP53 mutations and adverse outcome.
Comprehensive analysis of prognostic factors in myelodysplastic syndromes with isolated deletion of chromosome 5q.
Rbm5 sustains leukemia stem cells through a Myc-driven transcriptional circuitry.
Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results.
PAPOLA-mediated hyperactive polyadenylation promotes leukemogenesis and leukemia stem cell self-renewal through metabolic reprogramming.
Impact of conditioning regimen on outcomes of young AML patients ( < 40 years) undergoing HCT in complete remission, with transplant conditioning intensity score of 3.5-4.0. A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation.
SOHO State of the Art Updates and Next Questions | Progress in Higher-Risk Myelodysplastic Syndromes.
Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.
EIF4A3-dependent nonsense-mediated decay buffers AML1-ETO9a dosage and modulates outcome in t(8;21) acute myeloid leukemia.
Germline cancer risk alleles drive myelodysplastic neoplasms throughout adulthood.
The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML.
Prognostic impact of measurable residual disease in AML patients treated frontline with azacitidine and venetoclax: results from the French VENAURA registry.
Venetoclax-enhanced reduced-intensity conditioning in older patients aged ≥55 years with high-risk myeloid malignancies undergoing allogeneic peripheral blood stem cell transplantation: A phase II study.
Co-mutation signatures are age-dependent and impact the prognosis in NPM1-mutated acute myeloid leukemia: a PETHEMA multicenter study.
Cancer history and second cancer risk in polycythemia vera and essential thrombocythemia.
Magrolimab Plus Azacitidine Versus Placebo Plus Azacitidine in Patients With Untreated Higher-Risk Myelodysplastic Syndromes: The Phase III ENHANCE Study.
DHX15 affects AML1-ETO9a splicing together with HNRNPL, RBM33 in AML1-ETO-positive acute myeloid leukaemia.
Incidence, molecular and clinical characteristics of donor-derived hematologic malignancies after allogeneic stem cell transplantation for myeloid malignancies.
Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment-related pathways.
A novel combination approach targeting P300 and DNA-PK exploits epigenetic dependencies in acute myeloid leukemia.
Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
Frequency, kinetics, and clinical significance of HHV-6 DNAemia after PTCy-based hematopoietic cell transplant.
Hyperglycaemia as a predictor of morbidity and mortality in patients receiving an allogeneic haematopoietic stem cell transplantation.
R spondin 2 regulates regeneration of the hematopoietic stem cell niche.
Mutational profile and cardiovascular risk factors impact prognosis in triple-negative essential thrombocythemia.
A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
Metabolite glues as a means of purine sensing and chemotherapeutic response.
Socioeconomic inequality in treatment of acute myeloid leukaemia (AML) in England, 2015-2022: A population-based study.

Leukemia. 2026 Jul 13.

Subclonal MECOM rearrangements in myeloid neoplasms: enriched for TP53 mutations and adverse outcome.

Celina Eckfeld, Anna Stengel, Sandra Huber, Sophia Prohaska, Manja Meggendorfer, Torsten Haferlach, Isolde Summerer.

DOI: https://doi.org/10.1038/s41375-026-03057-3
Blood Adv. 2026 Jul 16. pii: bloodadvances.2026020633. [Epub ahead of print]

Comprehensive analysis of prognostic factors in myelodysplastic syndromes with isolated deletion of chromosome 5q.

Maria Julia Montoro, Victor Navarro, Pamela Acha, Claudia Haferlach, Onyee Chan, Yasuo Kubota, Felicitas Isabel Schulz, Robert Briski, Najla Al-Ali, Blanca Xicoy, Felix Lopez-Cadenas, Francesc Bosch, Anna Aguilera, Manja Meggendorfer, Lea Naomi Eder, Andrés Jerez, Yu Hung Wang, Alessia Campagna, Luca Lanino, Beate Betz, Valeria Santini, Teresa Bernal Del Castillo, Esperanza Such, Anne Sophie Platzbecker, Tariq Kewan, Carmelo Gurnari, Carla Zindel, Austin G Kulasekararaj, Maria Teresa Voso, Mikkael A Sekeres, Sangeetha Venugopal, Nicolas Diaz Varela, Aref Al-Kali, Uwe Platzbecker, Detlef Thomas Haase, Amer M Zeidan, Pierre Fenaux, María Díez-Campelo, Guillermo Garcia-Manero, Daniel Howard Wiseman, Matteo Giovanni Della Porta, Ulrich Germing, Jaroslaw P Maciejewski, Rami S Komrokji, Francesc Sole, Torsten Haferlach, Laura Palomo, David Valcarcel.

Myelodysplastic syndromes with isolated deletion of chromosome 5q [MDS-del(5q)] constitute a distinct biological entity traditionally associated with favorable outcomes, although up to one quarter of patients progress to acute myeloid leukemia (AML). Existing prognostic models, developed in heterogeneous MDS populations, may not adequately capture risk within this subgroup. We assembled an international cohort of 682 patients with MDS-del(5q) to evaluate the performance of the IPSS-R and IPSS-M, identify prognostic variables, and develop a disease-specific prognostic tool, the IPSS-del(5q). Most patients were classified as lower-risk by IPSS-R (94.4%) and IPSS-M (85.5%), yet both systems showed limited discriminatory ability (C-indices ≈0.5). Independent adverse prognostic factors included age ≥70 years, male sex, anemia (hemoglobin ≤10 g/dL), thrombocytopenia (platelets ≤100×10⁹/L), the presence of one additional chromosomal abnormality, ≥2 gene mutations, SF3B1 mutations, and high-risk TP53 status. Six variables were included in the IPSS-del(5q), stratifying patients into standard-risk (74.3%) and high-risk (25.7%) groups with significantly different LFS (69.2 vs. 32.0 months; p<0.01). Moreover, this model reclassified 19.1% of lower-risk IPSS-R and 14.6% of lower-risk IPSS-M patients into the high-risk IPSS-del(5q) group. However, its discriminative power remained modest, with a C-index of 0.60. Overall, this study provides the most comprehensive prognostic evaluation of MDS-del(5q) to date, demonstrates the limited discriminatory capacity of existing MDS scores in this entity, and underscores the need to develop refined disease-specific prognostic approaches for this MDS subtype.

DOI: https://doi.org/10.1182/bloodadvances.2026020633
Leukemia. 2026 Jul 16.

Rbm5 sustains leukemia stem cells through a Myc-driven transcriptional circuitry.

Mengli Zhang, Shaela Fields, Qiong Zhang, Yuxin Ouyang, Ye Xin, Jianxiang Zhang, Hong Liu, Jianfeng Shen, Beisi Xu, Jia Chen, Depei Wu, Chunliang Li, Peng Xu.

Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.

DOI: https://doi.org/10.1038/s41375-026-03064-4
Leukemia. 2026 Jul 16.

Asciminib monotherapy in patients with BCR::ABL1 T315I-mutated chronic-phase chronic myeloid leukemia: phase 1 trial final results.

Jorge E Cortes, Delphine Rea, Michael J Mauro, Andreas Hochhaus, Dong-Wook Kim, Koji Sasaki, Fabian Lang, Michael C Heinrich, Massimo Breccia, Michael Deininger, Yeow-Tee Goh, Jeroen J W M Janssen, Moshe Talpaz, Valle Gómez García de Soria, Philipp le Coutre, Francois-Xavier Mahon, Daniel J DeAngelo, Andrea Damon, Shruti Kapoor, Gessami Sanchez-Olle, Matthias Hoch, Nithya Agrawal, Sara Quenet, Timothy P Hughes.

In chronic myeloid leukemia in chronic phase (CML-CP), BCR::ABL1T315I commonly leads to treatment resistance, worse patient outcomes, and limited subsequent treatment options. By targeting the ABL1 myristoyl pocket, asciminib maintains activity against BCR::ABL1T315I. We report final long-term safety, tolerability, and efficacy results with asciminib in 48 patients with T315I-mutated CML-CP who received asciminib 200 mg twice daily in the phase 1, nonrandomized trial (NCT02081378). After a median exposure of 3.5 years, 52.1% of patients continued to receive asciminib via posttrial access. Of 45 evaluable patients, 24 (53.3%) achieved major molecular response (MMR); 20 of 24 maintained or deepened their response by the cutoff. The Kaplan-Meier estimated proportion of patients maintaining their first MMR for at least 144 weeks (2.8 years) was 86% (95% CI: 71.9-100.0%). The safety profile showed no new or worsening safety signals. With 1.4 years' additional exposure since the previous analysis, the incidence of grade ≥3 adverse events (AEs) (60.4%) did not increase. Four patients (8.3%) discontinued due to AEs. The exposure-adjusted incidence rate of first all-grade AOEs was 4.4 cases per 100 patient-years. With up to approximately 6 years of exposure, this final analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP.

DOI: https://doi.org/10.1038/s41375-026-02972-9
Nat Cancer. 2026 Jul 15.

PAPOLA-mediated hyperactive polyadenylation promotes leukemogenesis and leukemia stem cell self-renewal through metabolic reprogramming.

Siyao Guo, Yutong Zou, Canfeng Zhang, Hui Han, Yishan Li, Yucong Sun, Zhaoyu Wang, Wanrui Zhang, Jiang Zhang, Yuli Gan, Qiang Zhang, Jieyi Ma, Siyi Zheng, Hongshen Qiu, Yan Zhu, Wange Lu, Yong Bao, Meng Zhao, Shuibin Lin.

Polyadenylation is essential for mRNA stability and translational efficiency. Although poly(A) tail length is dynamically regulated under physiological conditions, its dysregulation and functional importance in cancer remain poorly understood. Here, we identify widespread poly(A) tail elongation and aberrant upregulation of poly(A) polymerase alpha (PAPOLA) in acute myeloid leukemia (AML), with high PAPOLA expression associated with poor clinical outcomes. Using primary AML samples, leukemia cell lines and multiple mouse models, we demonstrate that PAPOLA-driven hyperactive polyadenylation promotes leukemogenesis and sustains leukemia stem cell maintenance. Mechanistically, PAPOLA enhances metabolic reprogramming by upregulating glutathione S-transferase mu 2 (GSTM2), which activates the 4-hydroxynonenal (HNE)-dihydrolipoamide dehydrogenase (DLD) axis to drive AML progression. Notably, pharmacological inhibition of PAPOLA with cordycepin suppresses metabolic reprogramming and impairs leukemogenesis. Overall, our findings establish hyperactive polyadenylation as a core oncogenic mechanism linking RNA processing to cancer metabolism in AML, highlighting the PAPOLA-GSTM2-HNE-DLD axis as a promising therapeutic target.

DOI: https://doi.org/10.1038/s43018-026-01190-7
Bone Marrow Transplant. 2026 Jul 17.

Impact of conditioning regimen on outcomes of young AML patients ( < 40 years) undergoing HCT in complete remission, with transplant conditioning intensity score of 3.5-4.0. A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation.

Enrico Maffini, Maud Ngoya, Mohamed Houhou, Malek Benakli, Babak Bahar, Mahmoud Aljurf, Khalid Halahleh, Regis Peffault de Latour, Igor-Wolfgang Blau, Andrew Clark, Catherine Flynn, Peter Pal Remenyi, Maria Losa Maroto, Ibrahim Yakoub-Agha, Henrik Sengeloev, Cristina Castilla-Llorente, Emma Nicholson, Urpu Salmenniemi, Radovan Vrhovac, Jakob Passweg, Matthias Eder, Etienne Daguindau, Alexandros Spyridonidis, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.

The optimal myeloablative conditioning regimen for adolescents and young adults with acute myeloid leukaemia (AML) is currently unknown. In this retrospective analysis conducted on AML patients aged 18-40 years, in complete remission (CR), who received an allogeneic hematopoietic cell transplantation (HCT) we compared outcomes of different conditioning regimens. A total of 4323 patients, with median age of 30.9 years, transplanted from 2010 to 2022, received one of four regimens: high-dose total body irradiation (TBI)-based (n = 1031), thiotepa-busulfan (Bu)-fludarabine (Flu) (TBF) n = 219, Bu-Flu (n = 1100), and Bu-cyclophosphamide (Cy) (n = 1973). Prolonged OS and PFS for Bu-Flu (hazard ratio [HR] 0.73, 95% CI 0.57-0.92, p = 0.008; HR 0.78, 95% CI 0.64-0.94, p = 0.01), and TBF (HR 0.59, 95% CI 0.38-0.92, p = 0.02; HR 0.67, 95% CI 0.47-0.94, p = 0.02), respectively, as well as less RI for both Bu-Flu (HR 0.77, 95% CI 0.63-0.95, p = 0.01), and TBF (HR 0.68, 95% CI 0.47-0.99, p = 0.046). In conclusion, young adult AML patients seem to benefit from high dose TBI-free regimens, in terms of survival and toxicity, with four major myeloablative regimens. TBF and Bu-Flu were associated with better clinical outcomes, partly reflecting the general improvement in supportive therapies and patient selection introduced in recent years. Prospective clinical trials are warranted.

DOI: https://doi.org/10.1038/s41409-026-02991-1
Clin Lymphoma Myeloma Leuk. 2026 Jun 21. pii: S2152-2650(26)00184-9. [Epub ahead of print]

SOHO State of the Art Updates and Next Questions | Progress in Higher-Risk Myelodysplastic Syndromes.

Carlotta Pazzi, Amy E DeZern.

  Myelodysplastic syndromes (MDS) are clonal myeloid malignancies characterized by ineffective hematopoiesis and cytopenias, and possible risk of transformation to acute myeloid leukemia (AML). Higher-risk MDS (HR-MDS) carries significant morbidity and mortality with limited therapeutic options and poor outcomes following treatment failure. The Molecular International Prognostic Scoring System (IPSS-M) refined HR-MDS prognostication by retaining key clinical and cytogenetic variables from the IPSS-R while incorporating somatic mutation data with the inclusion of 16 additional "main effect" prognostic genes and 15 "residual" genes that confer additional risk when mutated. This molecular integration has reclassified risk categories for MDS, approximately upstaging one-third of patients. Concurrently, updated World Health Organization (WHO) and International Consensus Classification (ICC) frameworks have refined the MDS-AML diagnostic gray zone, with the ICC recognizing 10% to 19% bone marrow blasts as "MDS/AML overlap syndrome," broadening eligibility for clinical trials. A unified WHO and ICC classification framework is anticipated, and emerging AI-based classification tools may further support diagnostic accuracy. Treatment remains centered on hypomethylating agents and allogeneic hematopoietic stem cell transplantation (allo-SCT). Despite early promise, multiple agents have failed to show clinical benefit in phase 3 clinical trials. Most recently, the VERONA trial exploring venetoclax and azacitidine did not meet its overall survival endpoint; however, secondary analyses suggested potential benefits in younger patients, those with > 5% blasts, and those with ASXL1/RUNX1, TP53 mutations, supporting biomarker-driven trial design. Venetoclax-based regimens are currently under investigation as bridging and maintenance strategies for allo-SCT. Emerging targets include CDC-like kinases and CD123, which are under early phase evaluation.

Keywords:  Allo-SCT; IPSS-M; Molecular mutations; Myelodysplastic neoplasms; Venetoclax

DOI:  https://doi.org/10.1016/j.clml.2026.06.010
Leukemia. 2026 Jul 13.

Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Anna B Halpern, Megan Othus, Mary-Elizabeth M Percival, Cristina Ghiuzeli, Jacob S Appelbaum, Paul C Hendrie, Ryan D Cassaday, Max Smith, Kathryn Russell, Bart L Scott, Jason P Cooper, Joshua R Veatch, Siobán B Keel, Vivian G Oehler, Erik L Kimble, Raya Mawad, Roland B Walter.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

DOI: https://doi.org/10.1038/s41375-026-03044-8
Leukemia. 2026 Jul 14.

EIF4A3-dependent nonsense-mediated decay buffers AML1-ETO9a dosage and modulates outcome in t(8;21) acute myeloid leukemia.

Min Zhang, Yisheng Li, Bin Zhang, Chen Cai, Shuyi Li, Zhijie He, Xiangyu Meng, Chengguang Wang, Weichao Ding, Xiaoqi Wang, Xingli Dong, Yonghui Li, Li Yu.

t(8;21) acute myeloid leukemia (AML) is driven by AML1-ETO, which undergoes alternative splicing to generate AML1-ETO9a (AE9a), a truncated isoform with enhanced leukemogenic activity. Although t(8;21) AML is considered favorable-risk, clinical outcomes are heterogeneous, and AE9a expression varies markedly among patients. How cells restrain this oncogenic isoform remains unclear. Here, we identify nonsense-mediated mRNA decay (NMD) as an isoform-specific buffer of AE9a dosage. Inclusion of the ETO9a cassette exon introduces premature termination codons and generates an NMD-sensitive transcript. In primary t(8;21) AML CD34⁺ hematopoietic stem and progenitor cells, AE9a inclusion inversely correlated with NMD-factor expression, and high EIF4A3 expression was associated with improved overall survival specifically in t(8;21) AML, but not in other AML subtypes. Pharmacological inhibition of SMG1 or EIF4A3 and genetic depletion of NMD factors increased AE9a abundance in t(8;21) AML cell lines and primary patient cells, with cytoplasmic transcript accumulation and increased AE9a protein. Conversely, EIF4A3 overexpression reduced AE9a RNA and protein, restrained t(8;21) AML cell growth, spared healthy CD34⁺ progenitor expansion, and enhanced idarubicin sensitivity. These findings define EIF4A3-dependent NMD as a checkpoint linking RNA surveillance to oncogenic fusion-isoform dosage, leukemic fitness, and chemosensitivity in t(8;21) AML, providing a mechanistic explanation for clinical heterogeneity in t(8;21) AML. EIF4A3-dependent NMD buffers AE9a dosage and modulates t(8;21) AML cell fitness and chemosensitivity: Schematic model summarizing the proposed AE9a-NMD axis in t(8;21) AML. Alternative splicing of AML1-ETO generates the ETO9a cassette exon, producing a PTC-containing AE9a transcript. After nuclear export, ribosome engagement with the PTC-containing AE9a mRNA recruits the NMD machinery, including UPF factors, SMG factors, DHX34, and the exon-junction complex component EIF4A3. Efficient NMD promotes AE9a mRNA decay and limits AE9a protein accumulation. High EIF4A3/NMD activity therefore lowers AE9a dosage, restrains t(8;21) AML cell proliferation, enhances chemosensitivity to idarubicin, and is associated with improved patient survival. Conversely, impaired NMD activity permits AE9a accumulation and may increase leukemic fitness. This model defines an isoform-specific, NMD-buffered oncogenic dosage checkpoint in t(8;21) AML.

DOI: https://doi.org/10.1038/s41375-026-03051-9
Leukemia. 2026 Jul 13.

Germline cancer risk alleles drive myelodysplastic neoplasms throughout adulthood.

Taylor D Walker, Ashwin L Koppayi, Tilda E Carlelycke, Yogameenakshi Haribabu, Courtnee Rodgers, Zachary Hattig, Soma Das, Angela Lager, Jason X Cheng, Madina Sukhanova, Lucy A Godley.

DOI: https://doi.org/10.1038/s41375-026-03052-8
Clin Cancer Res. 2026 Jul 13.

The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML.

Bing Z Carter, Po Yee Mak, Suresh Satpati, Edward Ayoub, Steffen Boettcher, Lauren B Ostermann, Yue Wei, Guillermo Garcia-Manero, Torsten Haferlach, Kunal Rai, Michael Andreeff.

BACKGROUND: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into frontline therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. Methods used include flow cytometry-based cell viability assays, Western blot, reverse-phase protein arrays, RNA-sequencing, CyTOF single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models.
RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared to 5-azacytidine (5-AZA) in 5-AZA or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index<1). NTX-301 inhibits DNMT1 and increases p73, caspase-8/activated caspase-8 levels in TP53-WT and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both, xenograft and PDX models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared to 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared to 5-AZA-treated cells, and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels.
CONCLUSION: Data suggest that NTX-301 exerts potent anti-leukemia activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1 and inducing DNA damage responses and apoptosis, by inducing p53 signaling and demethylating LATS1/2, thus activating Hippo signaling.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4843
Leukemia. 2026 Jul 17.

Prognostic impact of measurable residual disease in AML patients treated frontline with azacitidine and venetoclax: results from the French VENAURA registry.

French AURAML group

Measurable residual disease (MRD) is a key prognostic marker in acute myeloid leukemia (AML), but its significance in patients treated with azacitidine and venetoclax (AZA/VEN) outside clinical trials remains unclear. We retrospectively analyzed 220 newly diagnosed AML patients from the French VENAURA registry who achieved composite complete remission and underwent MRD evaluation by multiparametric flow cytometry (MFC, LAIP/LSC) and/or NPM1 RT-qPCR. Cumulative MRD negativity was achieved in 62-67% of patients. Attaining MRD negativity at any time was strongly associated with superior overall survival (OS: 31.3 months vs 15.7 months (HR = 0.47) for LAIP, not reached vs 10.8 months (HR = 0.38) for NPM1; all p < 0.001) and lower cumulative incidence of relapse. Dual LAIP/LSC negativity (NEG/NEG) conferred the best outcomes compared to NEG/POS (HR = 0.36, p = 0.02), POS/NEG (HR = 0.24, p < 0.001) and POS/POS (HR = 0.26, p = 0.26) status. Importantly, MRD response mitigated the adverse prognostic impact of ELN 2024 intermediate/poor risk, with MRD-negative patients achieving outcomes comparable to favorable-risk cases. MRD kinetics (early vs late responders) did not affect survival, while G-CSF use improved MRD conversion and OS. In real-world AZA/VEN-treated AML, achieving deep MRD negativity, by MFC or NPM1 RT-qPCR, emerges as the dominant prognostic determinant, overriding baseline risk and supporting its integration into response-adapted strategies.

DOI: https://doi.org/10.1038/s41375-026-03024-y
Br J Haematol. 2026 Jul 15.

Venetoclax-enhanced reduced-intensity conditioning in older patients aged ≥55 years with high-risk myeloid malignancies undergoing allogeneic peripheral blood stem cell transplantation: A phase II study.

Jie Gao, Huiying Qiu, Yin Tong, Chongmei Huang, Baoxia Dong, Jiahua Niu, Kun Zhou, Yu Cai, Liping Wan, Xianmin Song, Jun Yang.

  Reduced-intensity conditioning (RIC) is associated with a high relapse rate in high-risk acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). It remains unclear whether venetoclax, an anti-leukaemic agent, can enhance RIC efficacy. A prospective, single-arm, phase 2 trial enrolled patients with high-risk AML or MDS, aged ≥55 years, who underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT). All patients received venetoclax-enhanced RIC (VEN-RIC), comprising venetoclax, busulfan, fludarabine, cytarabine and low-dose total body irradiation (TBI). Fifty patients (median age 62) were enrolled. At a median follow-up of 14.9 months, the 1-year progression-free survival (PFS) was 72.5%, while 1-year overall survival (OS) and graft-versus-host disease/relapse-free survival (GVHD/GRFS) were 73.8% and 56.9% respectively. The 1-year cumulative incidence of relapse and non-relapse mortality were 16.8% and 10.6%. The 180-day cumulative incidence of acute GVHD was 22.9%, while the 1-year cumulative incidence of chronic GVHD was 25.8%. Multivariable analysis showed TP53 mutation was the strongest predictor of worse OS, PFS and GRFS, as well as higher relapse. We conclude that VEN-RIC is feasible and associated with encouraging survival and a manageable safety profile, warranting confirmation in randomized studies.

Keywords:  allogeneic peripheral blood stem cell transplantation; myeloid malignancy; older patients; reduced‐intensity conditioning; venetoclax

DOI:  https://doi.org/10.1111/bjh.70690
Haematologica. 2026 Jul 16.

Co-mutation signatures are age-dependent and impact the prognosis in NPM1-mutated acute myeloid leukemia: a PETHEMA multicenter study.

José Vicente Gil, Claudia Sargas, Rosa Ayala, Norma Carmen Gutiérrez, José Antonio Pérez-Simón, María Teresa Gómez-Casares, María José Larrayoz, Esther Prados-de La Torre, Isabel Cano-Ferri, Irene Navarro, Cristina Gil, Teresa Bernal, Eduardo Rodríguez-Arbolí, Esther Pérez-Santaolalla, Rafael Colmenares, Mar Tormo, Juan Bergua, María Luz Amigo, Carlos Rodríguez-Medina, Josefina Serrano, Ana Yurena Oliva, Juan Manuel Alonso-Domínguez, Víctor Noriega, Lorenzo Algarra, Mayte Olave, María José García-Pérez, Carmen Couto, Ágata Almela, María García-Fortes, María Dolores Madrigal, María Lourdes Hermosín, Mercedes Colorado, Raimundo García-Boyero, Francisco Ibáñez, María Solé, Carmen Martínez-Chamorro, María Del Carmen Mateos, María Del Carmen García-Garay, Antonio Solana-Altabella, Beatriz Martín-Herreros, Joaquín Martínez-López, María Del Carmen Chillón, Elena Soria, Cristina Bilbao, María José Calasanz, Joaquín Sánchez-García, Eva Barragán, Pau Montesinos.

NPM1-mutated acute myeloid leukemia is genetically heterogeneous, and risk assessment remains focused exclusively on FLT3-ITD despite the potential role of other co-mutations. We retrospectively analyzed 1,360 adults from a multicenter cohort to map age-resolved co-mutation architecture and prognostic impact. Co-mutations were present in 97% of patients (median = 3 mutations) with DNMT3A (45%), FLT3-ITD (42%), TET2 (27%), and IDH2 (20%) predominating. RTK/RAS partners were enriched in younger adults, whereas myelodysplasia-related genes (MR-genes), epigenetic lesions and higher mutation burden accumulated in the elderly. Pairwise co-mutations mapped to distinct clinical phenotypes with NPM1+FLT3-ITD showing a hyperproliferative profile, and NPM1+SRSF2/TET2 associated to older patients with cytopenic disease. In the 688 patients receiving upfront intensive therapy, NPM1 type Non-ABD exhibited a tendency toward poorer OS compared with type A. In competing-risk models, SRSF2 and DNMT3A were associated with a higher cumulative incidence of relapse (CIR). Consistently, multivariable analyses showed that increasing age and SRSF2 independently conferred adverse risk across OS, RFS, and EFS; KRAS adversely impacted OS, whereas FLT3-OTHER was associated with improved OS; and DNMT3A with inferior RFS and EFS but not OS. These findings show that co-mutation signatures in NPM1-mutated AML are age-structured and clinically meaningful, refining risk beyond FLT3-ITD.

DOI: https://doi.org/10.3324/haematol.2026.301025
Blood Cancer J. 2026 Jul 11.

Cancer history and second cancer risk in polycythemia vera and essential thrombocythemia.

Giuseppe G Loscocco, Fnu Aperna, Moazah Iftikhar, Priyansh Faldu, Masooma S Rana, Amritpal Singh, Tiziano Barbui, Paola Guglielmelli, Alessandro M Vannucchi, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi.

Patients with myeloproliferative neoplasms (MPN), including polycythemia vera (PV) and essential thrombocythemia (ET), have an increased risk of second cancers (SC), although determinants of risk remain incompletely defined. We retrospectively analyzed 1968 consecutive patients with PV or ET (median follow-up 11.2 years) to identify predictors of SC. Cumulative incidence functions were estimated using competing-risk methodology, and predictors were assessed using Fine-Gray regression. During follow-up, SC occurred in 404 patients (20%), with non-melanoma skin cancer (NMSC) representing the most frequent subtype. In multivariable models including all cancer types, prior cancer (sHR 2.02, p < 0.001), older age (per 10 years: sHR 1.20, p < 0.001), male sex (sHR 1.39, p = 0.002), and hyperlipidemia (sHR 1.41, p = 0.003) independently predicted SC. After excluding NMSC, prior cancer remained associated with SC risk (sHR 1.48, p = 0.048). Notably, prior NMSC strongly predicted subsequent NMSC (sHR 6.48, p < 0.001), followed by prior non-NMSC cancer (sHR 2.11, p < 0.001), age (sHR 1.29, p < 0.001), and male sex (sHR 1.43, p = 0.018). TET2 mutations showed a borderline association with NMSC risk (sHR 1.73, p = 0.055), while hydroxyurea was not associated with SC, with a non-significant trend toward increased NMSC risk (sHR 1.82, p = 0.110). These findings support risk-adapted cancer surveillance in PV and ET, with particular emphasis on regular dermatologic monitoring.

DOI: https://doi.org/10.1038/s41408-026-01560-5
J Clin Oncol. 2026 Jul 13. JCO2500617

Magrolimab Plus Azacitidine Versus Placebo Plus Azacitidine in Patients With Untreated Higher-Risk Myelodysplastic Syndromes: The Phase III ENHANCE Study.

David A Sallman, Guillermo Garcia-Manero, Naval Daver, Camille N Abboud, Eytan Stein, Karilyn Larkin, Anna B Halpern, Shannon R McCurdy, Monzr M Al Malki, Guru Subramanian Guru Murthy, Lewis R Silverman, Richard A Larson, Peter Greenberg, Ivana Gojo, Tomasz Wrobel, Uwe Platzbecker, Cecily Forsyth, Pankit Vachhani, Mei Dong, Jiang Shao, Lisa D S Johnson, Anderson Tan, Calvin Lee, Parul Doshi, Paresh Vyas, Andrew H Wei.

PURPOSE: To evaluate the efficacy and safety of the cluster of differentiation 47-targeted antibody magrolimab plus azacitidine (Magro/Aza) versus azacitidine alone in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) in the phase III ENHANCE study (ClinicalTrials.gov identifier: NCT04313881).
METHODS: Based on the Revised International Prognostic Scoring System, patients with intermediate- to very-high-risk MDS were randomly assigned to receive Magro (1 mg/kg on days [D]1 and 4; 15 mg/kg on D8; 30 mg/kg on D11 and D15, and then once per week for five doses, followed by 30 mg/kg maintenance doses once every 2 weeks)/Aza (75 mg/m2 daily on D1-7 or on D1-5 and 8-9 in 28-day cycles) or matched placebo plus azacitidine (Placebo/Aza). Dual primary end points were complete remission (CR) rate (per 2006 International Working Group criteria) and overall survival (OS).
RESULTS: At final analysis, 539 patients were randomly assigned to Magro/Aza (n = 268) or Placebo/Aza (n = 271) arms. Baseline characteristics were generally well balanced between treatment arms. In the Magro/Aza versus Placebo/Aza arms, the CR rate was 21.3% versus 23.6% (odds ratio, 0.876 [95% CI, 0.585 to 1.312]; P = .5218), and median OS was 15.9 versus 18.6 months (hazard ratio, 1.203 [95% CI, 0.947 to 1.528]; P = .1299). Magro/Aza had a higher incidence of grade ≥3 adverse events (AEs; 92.8% v 79.2%), AE-associated study drug discontinuations (24.0% v 12.1%), serious AEs (71.9% v 51.5%), and fatal AEs (15.2% v 9.8%) versus Placebo/Aza.
CONCLUSION: ENHANCE did not meet the primary end points of CR rate and OS, and showed more frequent severe AEs in patients treated in the Magro/Aza arm.

DOI: https://doi.org/10.1200/JCO-25-00617
Br J Haematol. 2026 Jul 12.

DHX15 affects AML1-ETO9a splicing together with HNRNPL, RBM33 in AML1-ETO-positive acute myeloid leukaemia.

Qiao Liu, Xuechun Wang, Jiqiang Fan, Yi Zheng, Luya Ye, Wenhan Chang, Xianglei Chen, Yuanhua Cai, Xiaolin Lai, Yang Li, Lili Pan, Xiaofan Li, RenJang Lin, Shaoyuan Wang.

  The AML1-ETO (AE) fusion gene, resulting from t(8;21)(q22;q22), represents a prevalent subtype of acute myeloid leukaemia (AML). Retention of exon 9a between exon 8 and 9 of the ETO (RUNX1 Partner Transcriptional Co-Repressor 1, also name RUNX1T1) gene generates the oncogenic AML1-ETO9a (AE9a) splice variant. Here, we uncover the potential involvement of RNA (ribonucleic acid) helicase DHX15 (DEAH-box helicase 15) in AE9a splicing and AML progression. Clinically, higher expressed DHX15 is associated with increased AE9a/AE abundance and poor outcomes in AE-positive (AE+) AML patients. DHX15 knockdown impaired cell proliferation, induced S/G2 cell-cycle arrest in vitro and prolonged overall survival in AE+ leukaemia-bearing mice in vivo. In addition, DHX15 knockdown reduced AE and AE9a expression, and RNA immunoprecipitation revealed DHX15 bound to AE and AE9a transcripts and RNA pull-down assay showed a selective interaction of HNRNPL and RBM33 with AE9a transcripts. Three-dimensional structure prediction suggests a sophisticated regulatory complex formation involving DHX15, HNRNPL (heterogeneous nuclear ribonucleoprotein L) and RBM33 (RNA binding motif protein 33). Further, HNRNPL and RBM33 gene expression positively correlated with AE9a levels in AE+ AML samples. Downregulation of HNRNPL and RBM33 reduced AE9a expression in Kasumi-1 cells. Collectively, our findings support an association between DHX15, HNRNPL, RBM33 and AE9a splicing and suggest their contribution to leukemogenic progression in AE+ AML.

Keywords:  AML; AML1‐ETO; AML1‐ETO9a; DHX15; RNA splicing

DOI:  https://doi.org/10.1111/bjh.70658
Haematologica. 2026 Jul 16.

Incidence, molecular and clinical characteristics of donor-derived hematologic malignancies after allogeneic stem cell transplantation for myeloid malignancies.

Tetiana Perekhrestenko, Anita Badbaran, Evgeny Klyuchnikov, Catherina Lück, Ina Rudolph, Silke Heidenreich, Jochim Reinert, Radwan Massoud, Dietlinde Janson, Christine Wolschke, Manja Meggendorfer, Torsten Haferlach, Nicolaus Kröger, Francis Ayuk, Boris Fehse.

Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative approach for several high-risk hematologic malignancies, but high relapse rates remain a challenge. Most relapses derive from the original malignant clone or its descendants. Occasionally, secondary blood cancers arise from transplanted donor cells and are referred to as donor-derived malignancies (DDMs). To assess the incidence of DDM at our center we performed a retrospective observational study on all evaluable patients allo-transplanted for myeloid malignancies in the Dept. of SCT of UMC Hamburg-Eppendorf between 1990 and 2024. Until the end of the observation (12/2025), we observed 791 relapses after 2827 allo-SCTs (28%). For 751 (94.9%) of the relapses, material was available for detailed molecular analysis. Three myeloid malignancies (CMML, MDS, AML) were unambiguously identified as DDMs (two from matched related, one from an unrelated donor) corresponding to low frequencies of 0.1% of all transplants and 0.4% of analyzed relapses. Notably, in no case we found mutations in typical germline predisposition genes (DDX41, RUNX1, GATA2, CEBPA), whereas mutations associated with CHIP (ASXL1, TET2, DNMT3A, CBL, U2AF1) were detected in all DDMs. In conclusion, comprehensive data from this - to our knowledge largest - single-center study covering almost 3,000 consecutive transplants over a period of 35 years supports a low overall incidence of DDMs and a potential role of donor-derived clonal hematopoiesis in their development.

DOI: https://doi.org/10.3324/haematol.2026.301087
Br J Haematol. 2026 Jul 14.

Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment-related pathways.

Trinayan Kashyap, Andrea A Ellero, Christopher J Walker, Marie E Maloof, Min Lu, Lijuan Xia, Ronald Hoffman, Pietro Taverna.

  Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, marrow fibrosis, cytopenias and inflammation. Janus kinase 2 (JAK2) inhibitors, such as ruxolitinib, reduce splenomegaly and alleviate symptoms but have limited disease-modifying activity, and resistance frequently develops. Selinexor, an oral selective exportin (XPO1) inhibitor, restores nuclear retention of tumour suppressors and inhibitors of inflammatory signalling. Dual XPO1/JAK2 inhibition targets complementary downstream pathways, enhancing suppression of MF progenitor cell fitness. We evaluated selinexor plus ruxolitinib in MF models, including JAK2V617F or calreticulin (CALR) exon 9-mutant MPN cell lines and samples from patients with MF. The combination showed greater anti-proliferative activity than JAK2 inhibition alone and suppressed colony formation from MF Cluster of Differentiation 34 (CD34)+ cells. Selinexor remained active in a ruxolitinib-resistant MPN cell line, inducing G1 arrest and apoptosis. Multi-omic analyses demonstrated increased nuclear retention of p53 and disruption of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling, complementing and extending ruxolitinib-targeted pathways. The combination suppressed NF-κB transcriptional activity and reduced Tumor Necrosis Factor alpha (TNFα), Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1) secretion from MF patient peripheral blood mononuclear cells. These findings highlight that selinexor plus ruxolitinib affects both MF haematopoietic cell-intrinsic and microenvironment-related pathways, providing a novel disease-modifying strategy with the potential to improve clinical outcomes in patients with MF.

Keywords:  JAK/STAT; NF‐κB; exportin 1; myelofibrosis; p53; ruxolitinib; selinexor

DOI:  https://doi.org/10.1111/bjh.70639
Mol Ther Oncol. 2026 Sep 17. 34(3): 201262

A novel combination approach targeting P300 and DNA-PK exploits epigenetic dependencies in acute myeloid leukemia.

Srinivas Vinod Saladi, Swati Garg, Ellen L Weisberg, Abigail E Case, Wei Ni, Siddhika Pareek, Klaus Podar, Ravi Salgia, James D Griffin, Richard M Stone, Martin Sattler.

  Acute myeloid leukemia (AML) is characterized by poor survival, especially in older patients with relapse/refractory disease. With an apparent lack of reliable long-term treatments, pathways involved in chromatin regulation represent potentially leverageable targets. The arginine methyltransferase CARM1 is a known dependency in AML, yet clinical grade inhibitors have remained elusive. We found that CARM1 promotes DNA repair and other pathways associated with malignant growth. Dysregulation of DNA repair pathways is pervasive in AML and linked to the transforming phenotype. Interestingly, targeting CARM1 chemosensitized AML cells for DNA-PK inhibition by peposertib, thereby blocking NHEJ (non-homologous end joining). Also, H3K27ac (histone H3 lysine 27 acetylation) active enhancer marks and marks of the corresponding histone acetyltransferase, P300, were found at the promoter region of relevant CARM1-regulated DNA repair enzymes. Consequently, our results show that CARM1 dependencies could also be exploited by utilizing inobrodib, a p300/CBP bromodomain inhibitor that synergizes with peposertib treatment in AML cells. Overall, these data demonstrate a rational approach for combination therapy by exploiting dependencies through inhibition of proximal effector function in addition to essential NHEJ repair, targeting its rate-limiting enzyme complex, thereby resulting in synergistic inhibition in primary AML.

Keywords:  CARM1; DNAPK; EP300; acute myeloid leukemia; inobrodib; peposertib

DOI:  https://doi.org/10.1016/j.omton.2026.201262
Nat Aging. 2026 Jul 16.

Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.

Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, Clair Tsui, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen.

Trained immunity is a state of heightened immune response that is initiated in hematopoietic stem cells (HSCs) and mediated mainly by their myeloid progeny. Aging-associated inflammation drives many aging-related diseases, yet its biological origin is largely unknown. Here we show that SIRT3, a mitochondrial deacetylase highly expressed in HSCs but reduced during aging, suppresses the HSC response to aging that drives maladaptive trained immunity, chronic inflammation and tissue functional decline in mice. Overexpression of SIRT3 in HSCs not only ameliorates aging-associated HSC decline, but also improves the function of distant tissues, including attenuation of age-related declines in cognition and motility, via myeloid cells with modulated inflammatory programs. These findings reveal that HSC aging is a driver of aging-associated inflammation through maladaptive trained immunity and broaden the possible clinical applications of targeting HSCs from hematological diseases to include countering aging-associated physiological decline and improving healthspan.

DOI: https://doi.org/10.1038/s43587-026-01175-2
Blood Adv. 2026 Jul 17. pii: bloodadvances.2025018166. [Epub ahead of print]

Frequency, kinetics, and clinical significance of HHV-6 DNAemia after PTCy-based hematopoietic cell transplant.

Elisabetta Xue, Sanchita Das, Hyoyoung Choo-Wosoba, Dimana Dimitrova, Mustafa A Hyder, Francis A Flomerfelt, Brian Dawson, William Telford, Kalpana Dulal Upadhyaya, Kamil Rechache, Christopher G Kanakry, Jennifer A Kanakry.

The clinical significance of human herpesvirus-6 (HHV-6) after allogeneic hematopoietic cell transplantation (HCT) is debated. We prospectively collected weekly whole-blood HHV-6 in 217 PTCy-based HCT recipients. One-hundred forty-nine (69%) patients had at least one detection, at a median of 21 days post-HCT, and 63 (29%) spiked ≥4*log10 copies/mL (high-level HHV-6 DNAemia) at median day +27. Hematologic malignancy, myeloablative conditioning, HLA-partially-mismatched donor, marrow graft, PTCy dose, and sirolimus use were associated on univariate analysis with high-level HHV-6 DNAemia. All spikes precipitously declined spontaneously, but after initial decline, 27% persisted at ≥3*log10 copies/mL for >1 month. Those with HHV-6 spikes had lower day +28 CD4+ T-cell counts. During initial spikes, there was a strong correlation between plasma and whole blood HHV-6 DNAemia (Spearman's ρ=0.85, p<0.0001). By contrast, in patients with HHV-6 persisting >1 month, HHV-6 was predominantly found within CD4+ T-cells, but not in plasma. Only one patient developed HHV-6-associated encephalitis, but high-level HHV-6 DNAemia was associated with increased rates of otherwise unexplained fever (35% vs 21% in patients without high-HHV-6 DNAemia, p=0.036), rash (27% vs 12%, p=0.009), transaminitis (52% vs 27%, p=0.001), and gastrointestinal symptoms (23% vs 7%, p=0.0036) as well as increased risk of acute (36% vs 18%, p=0.007) and moderate-to-severe chronic (22% vs 8%, p=0.01) graft-versus-host disease. HHV-6 detection occurs frequently in PTCy-recipients but infrequently leads to classic HHV-6-related disease (encephalitis), although it associates with various self-limited clinical symptoms, may play a role in shaping immune reconstitution, and may serve as a marker for increased GVHD risk. (NCT04959175, NCT05436418, NCT02579967, NCT03983850, NCT03922724, NCT03663933).

DOI: https://doi.org/10.1182/bloodadvances.2025018166
Br J Haematol. 2026 Jul 17.

Hyperglycaemia as a predictor of morbidity and mortality in patients receiving an allogeneic haematopoietic stem cell transplantation.

Marieke Tienstra, Fleur R Goemans, Kylie Keijzer, Inge V G Oteman, Carin L E Hazenberg, Jaap A van Doesum, Anne G H Niezink, Goda Choi, Gerwin A Huls, Peter R van Dijk, Hilde A M Kooistra, Tom van Meerten, Linde M Morsink.

  Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for patients with haematological malignancies; however, post-transplant complications, including infections and acute graft-versus-host disease (aGvHD), remain significant issues. Identifying modifiable risk factors is therefore critical to improve patient outcomes. This retrospective study evaluated the impact of hyperglycaemia on post-transplant outcomes in adult patients undergoing allo-HSCT at the University Medical Centre Groningen between 2018 and 2024. Hyperglycaemia was defined as a glucose level exceeding 10 mmol/L in capillary or venous samples. In total, 575 patients were included. The median age was 61 years (interquartile range [IQR]: 52-68); 64% were male, and the median body mass index (BMI) was 25.3 kg/m2 (IQR: 23.1-28.0). During hospitalization, 26.6% of patients experienced at least one episode of hyperglycaemia. After adjusting for confounding variables, hyperglycaemia was associated with significantly reduced 100-day overall survival (hazard ratio [HR] 2.36, 95% confidence interval [CI] 1.29-4.33). It was also linked to an increased risk of severe (grade ≥3) aGvHD and infections. Importantly, hyperglycaemia occurring within 30 days prior to transplantation already predicted poorer survival. In conclusion, hyperglycaemia at any moment during allo-HSCT is predictive for treatment-related adverse events. Since glucose levels are highly modifiable, closer attention and timely intervention might improve outcomes.

Keywords:  hyperglycaemia; risk factor; transplantation

DOI:  https://doi.org/10.1111/bjh.70692
Blood. 2026 Jul 01. pii: blood.2025032421. [Epub ahead of print]

R spondin 2 regulates regeneration of the hematopoietic stem cell niche.

Vanessa N Montinelli, Samantha Grohe, Xue Ying Song, Jacqueline Judith Turnlund, Hannah Hackbart, Joshua P Sasine, Morgan Brady, Masahiro Muraoka, Rucha Kadam, Flavia Cavicchioli, Sage Victoria Kang, Ashley Dawson, Mimoli Ellise Uehara, Courtny Dizon, Kurt Hankenson, Theresa Krack, Peibin Yue, Yuwei He, John P Chute.

Hematopoietic stem cells (HSCs) depend upon paracrine signals from bone marrow endothelial cells (BM ECs) and perivascular stromal cells for their maintenance and regeneration. Chemotherapy and total body irradiation (TBI) utilized in the curative treatment of cancer cause profound damage to the BM vascular niche, which impedes hematopoietic reconstitution. The mechanisms controlling regeneration of the HSC vascular niche are not well understood. We discovered that conditional deletion of R spondin 2 (Rspo2) from BM endothelial cells (ECs) impaired HSC regeneration in mice following total body irradiation (TBI), in association with decreased HSC survival. Mice lacking EC - Rspo2 expression demonstrated delayed regeneration of the BM vascular niche following TBI and Rspo2 - deficient BM ECs displayed defective angiogenesis. Conversely, systemic administration of R spondin 2 caused early restoration of the BM sinusoidal vascular niche in irradiated mice and augmented BM EC angiogenesis. Concordantly, R spondin 2 - treated mice displayed accelerated regeneration of the HSC pool. These studies suggest that BM ECs regulate the regeneration of the BM sinusoidal vascular niche via secretion of R spondin 2.

DOI: https://doi.org/10.1182/blood.2025032421
Leukemia. 2026 Jul 13.

Mutational profile and cardiovascular risk factors impact prognosis in triple-negative essential thrombocythemia.

MPN Spanish Group (GEMFIN)

Triple-negative essential thrombocythemia (TN-ET) represents a diagnostic and therapeutic challenge. The aim of the present study was to identify prognostic factors useful for tailoring treatment. 241 TN-ET patients with myeloid panel sequencing and confirmatory bone marrow biopsy were selected. Pathogenic/likely pathogenic variants were identified in 19.5% of patients. Mutation carriers were older (median age 66 years vs. 53, p < 0.001) and had a higher frequency of prior thrombosis (19.6% vs. 6.5%, p = 0.013). Presence of pathogenic/likely pathogenic variants was associated with leukemic progression (HR 12.608; 95% CI: 2.616-60.775, p = 0.002) and lower overall survival (HR 3.008; 95% CI: 1.43-6.327, p = 0.004). ASXL1 (p = 0.004), CBL (p < 0.001), EZH2 (p < 0.001), and ZRSR2 (p < 0.001) mutations were associated with inferior leukemia-free survival. Age over 60 years, previous thrombosis, and cardiovascular risk factors were associated with higher thrombotic risk. Revised IPSET-thrombosis was useful for risk stratification (10-year probability of overall thrombosis: 30%, 15%, and 6% for high-, intermediate-, and very-low risk patients, respectively, p < 0.001). ARTS score refined arterial thrombosis stratification (10 years probability: 25% and 6% for high- and low-risk, respectively, p < 0.001). Progression to myelofibrosis was a rare event in this cohort (2.5%). These results highlight the biological and prognostic relevance of molecular profile in TN-ET.

DOI: https://doi.org/10.1038/s41375-026-03035-9
Science. 2026 Jul 16. 393(6808): eadx8675

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.

Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.

The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.

DOI: https://doi.org/10.1126/science.adx8675
Nature. 2026 Jul 15.

Metabolite glues as a means of purine sensing and chemotherapeutic response.

Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.

Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.

DOI: https://doi.org/10.1038/s41586-026-10790-3
Br J Haematol. 2026 Jul 14.

Socioeconomic inequality in treatment of acute myeloid leukaemia (AML) in England, 2015-2022: A population-based study.

Koki Shimizu, Mari Kajiwara Saito, Camille Maringe, Yasushi Miyazaki, Bernard Rachet.

  The socioeconomic inequality in acute myeloid leukaemia (AML) survival may be driven by differential access to intensive chemotherapy (ICT). We aimed to quantify socioeconomic inequality in the receipt of ICT among patients with AML in England and identify its key drivers. We evaluated 10 495 patients with de novo AML identified in the national cancer registry of England (2015-2022) along with their area-deprivation status, as a measure of socioeconomic inequality, and treatment information based on linkage databases. We related prevalence of the ICT receipt to deprivation with multivariable-adjusted generalised regression and mixed-effects probit regression. Overall, 5190 patients (49%) received ICT. The patients in the most deprived area were 6.1% less likely to receive ICT than those in the least deprived area. The differences in the prevalence measures varied across the 125 administrative clusters of health service units. If all patients had access to ICT similar to the least deprived patients, 247 more patients would receive ICT. Of the deprivation effect, 94% was estimated to be attributable to the variability among administrative clusters. Despite universal healthcare coverage, socioeconomic inequality exists in AML treatment in England. The inequality may be driven by cluster-level variations such as institutional culture and resource capacity.

Keywords:  England; NHS Trust; acute myeloid leukaemia; socioeconomic inequalities

DOI:  https://doi.org/10.1111/bjh.70695