bims-tremyl 2025-08-03 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–08–03
forty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

XPO1 Drives Resistance to Eprenetapopt and Azacitidine and Can Be Targeted in TP53-Mutated Myeloid Malignancies.
Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.
Secondary and therapy-related acute myeloid leukemias: Overlapping features, distinct trajectories.
Current Treatment Strategies for FLT3-Mutated Acute Myeloid Leukemia in Patients not Candidates for Intensive Chemotherapy.
Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness.
Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.
Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
ALKBH1 drives tumorigenesis and drug resistance via tRNA decoding reprogramming and codon-biased translation.
A specific bone marrow cytokine pattern in de novo acute myeloid leukemia.
Disease risk but not remission status determines transplant outcomes in AML: long-term outcomes of the ASAP trial.
Somatic Mutations in STAG2 Are Associated with Separated Megakaryocyte Nuclear Lobes in Myelodysplastic Syndromes.
Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions.
Time to complete remission is an independent determinant of survival after intensive chemotherapy in AML.
Avapritinib versus midostaurin or cladribine in advanced systemic mastocytosis: A retrospective real-world external control study.
Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
A clinico-genomic prognostic model for primary myelodysplastic neoplasm in Asia.
MDM4 overexpression alleviates developmental and hematopoietic defects in Fancg deficient mice.
HiJAKing the Hematopoietic System: A Low-Frequency JAK2V617F Clone Drives Myeloproliferative Neoplasm Pathology.
Cost-Effectiveness of Upfront vs. Delayed Allogeneic Hematopoietic Stem Cell Transplant for Intermediate Risk AML.
Replication of a GWAS signal near HLA-DQA2 with AML using a disease-only cohort and external population-based controls.
Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression in patients.
SUGP1 loss drives SF3B1 hotspot mutant missplicing in cancer.
Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death.
A molecular-based risk score for predicting leukemia-free survival in adult AML patients undergoing Allo-HSCT.
Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML.
Menin inhibitors in KMT2A-rearranged leukemia: Mechanistic insights, clinical trial progress, and potential of combination therapies.
Assessment of peripheral blood DNA methylation signatures as pharmacodynamic and predictive biomarkers during azacitidine therapy in juvenile myelomonocytic leukaemia: Results of the EWOG-MESRAT study.
Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency.
A clinical guide to TP53 mutations in myeloid neoplasms.
Outcomes with intensive chemotherapy, compared to hypomethylating agent + venetoclax, in patients with intermediate and adverse risk acute myeloid leukemia.
Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia.
Bisantrene in combination with fludarabine and clofarabine as salvage therapy for adult patients with refractory or relapsed acute myeloid leukaemia (AML)-An open-label, phase I/II study.
Transcriptomic landscape of CD8+ and CD4 + T-LGL leukemia revealed the distinct impact of STAT3 and STAT5B activating mutations.
Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.
The importance of systemic inflammatory response measurements as pretransplant risk factors for outcome after allogeneic haematopoietic cell transplantation.
Pilot study of an inpatient physical activity intervention for older adults treated intensively for acute myeloid leukemia.
Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting.
Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome.
Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
Evaluating a predictive model of tyrosine kinase inhibitor therapy failure in a European-type cohort: a step towards population-specific tools.

Blood. 2025 Jul 30. pii: blood.2025028803. [Epub ahead of print]

XPO1 Drives Resistance to Eprenetapopt and Azacitidine and Can Be Targeted in TP53-Mutated Myeloid Malignancies.

Traci L Kruer, Ariel Quintana-Gonzalez, Hannah L Newman, Meghan C Ferrall-Fairbanks, Ling Zhang, Amy F McLemore, Surendra Neupane, Qin Yang, Nana Adjoa Ben-Crentsil, Maria E Balasis, Christopher T Letson, Rami S Komrokji, Sana Chaudhry, Tulasigeri M Totiger, Joshua A Traina, Maria E Figueroa, Christopher B Ryder, Thomas Cluzeau, Justin Taylor, David A Sallman, Eric Padron.

TP53 mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most aggressive and chemotherapy refractory myeloid neoplasms with a median overall survival of less than 6 months. An enormous unmet need exists to develop novel therapeutic strategies and understand resistance mechanisms to suboptimal existing therapies for this disease. In two parallel phase 2 clinical trials that combined eprenetapopt with azacitidine in TP53 mutated MDS/AML, we observed complete remission rates of 40-50% and molecular remission rates of 38%. However, unless allogeneic stem cell transplantation was performed, relapse inevitably occurred. To understand the mechanisms of secondary resistance responsible for this, we genotyped sequential clinical trial samples, conducted a genome-wide CRISPR screen in TP53 mutated leukemia cells, and identified XPO1 as a therapeutically tractable mediator of resistance. We demonstrate that XPO1 is overexpressed in patient samples after eprenetapopt and azacitidine treatment, elucidate the mechanism by which this occurs, and determine that it is necessary and sufficient for resistance to combination therapy. Finally, we validate in a variety of model systems including a novel patient derived xenograft model of TP53 mutant MDS, that eprenetapopt in combination with XPO1 inhibitors can overcome this resistance, providing preclinical rationale that this novel combination strategy is a viable therapeutic approach in TP53 mutant MDS/AML patients.

DOI: https://doi.org/10.1182/blood.2025028803
Gene. 2025 Jul 25. pii: S0378-1119(25)00474-3. [Epub ahead of print]966 149685

Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.

Huasong Yu, Lin Yan.

  AML (Acute myeloid leukemia) is an aggressive cancer of the blood and bone marrow characterized by the excessive proliferation of immature white blood cells, that disrupt normal hematopoiesis. LSCs (Leukemic stem cells) represent a subpopulation of AML cells with stem cell-like properties that drive AML initiation, progression, and relapse by evading conventional therapies and sustaining leukemic growth. Despite advances in understanding AML biology, particularly their metabolic alternations, remain poorly understood. Indeed, recent studies have shown that mitochondrial metabolism plays a pivotal role in the regulation of both normal HSCs (hematopoietic stem cells) and LSCs. In this review, we delve into the mitochondrial metabolic characteristics of normal HSCs to provide comprehensive background knowledge. Subsequently, we thoroughly analyze how the distinctive metabolic features of LSCs, highlighting the impact of these differences on cell function and survival. We also investigate the unique mechanisms of drug resistance in LSCs, explaining how these mechanisms enhance the survival of LSCs in the face of conventional treatments. Finally, we discuss emerging therapeutic strategies targeting the mitochondrial metabolism of LSCs in AML, and we discuss prospective therapeutic strategies and future research directions.

Keywords:  Acute myeloid leukemia; Hematopoietic stem cell; Leukemia stem cell; Metabolism; Mitochondria; Mitochondrial quality control

DOI:  https://doi.org/10.1016/j.gene.2025.149685
Semin Hematol. 2025 Jun 30. pii: S0037-1963(25)00032-0. [Epub ahead of print]

Secondary and therapy-related acute myeloid leukemias: Overlapping features, distinct trajectories.

Luca Guarnera, Emiliano Fabiani, Giorgia Silvestrini, Enrico Attardi, Maria Teresa Voso.

  Therapy-related acute myeloid leukemia (tAML) and AML arising from previous hematologic disorders (secondary AML, sAML) share similar biological features, including karyotype abnormalities and gene specific mutations, patient-related risk factors. Older age and lower performance status also contribute to dimal prognosis, and dismal prognosis, both in terms of response rate and overall survival. However, these 2 entities significantly differ in leukemogenic trajectories. In this line, recent advances allowed for a better understanding of differential clonal progression processes in the broad landscape of sAMLs. Thus, in this manuscript, we reviewed clinical and biological characteristics of tAML and sAML, highlighting commonalities and divergent features and discussed classification aspects. We also gathered the newest evidence of leukemogenic trajectories leading from bone marrow failure syndromes, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and MDS/MPN overlap syndromes to sAML, as well as leukemias arising from donors' cells in the setting of allogenic transplantation. Furthermore, we reviewed germline and acquired predisposition to leukemias and discussed the therapeutic landscape and future directions.

Keywords:  Acute myeloid leukemia postcytotoxic therapy; Secondary acute myeloid leukemia; Therapy-related acute myeloid leukemia

DOI:  https://doi.org/10.1053/j.seminhematol.2025.06.005
Curr Oncol Rep. 2025 Aug 01.

Current Treatment Strategies for FLT3-Mutated Acute Myeloid Leukemia in Patients not Candidates for Intensive Chemotherapy.

Alex Bataller, Nicholas J Short, Naval Daver, Musa Yilmaz, Hagop Kantarjian, Farhad Ravandi.

   PURPOSE OF REVIEW: Younger patients with acute myeloblastic leukemia with FLT3 mutations (FLT3-mutated AML) benefit from the addition of FLT3 inhibitors to intensive chemotherapy. However, patients who are not eligible for intensive chemotherapy have poor outcomes with standard low-intensity treatments. In this review we assess the current state of treatment strategies for patients with FLT3-mutated AML who are not candidates for intensive chemotherapy.
RECENT FINDINGS: The addition of FLT3 inhibitors to standard low-intensity AML treatments (doublet) has increased response rates, although in a randomized clinical trial this did not improve survival. The addition of venetoclax to these regimens (triplet) shows promising activity (overall response rate of approximately 90%). However, myelotoxicity is common, and dose adjustments are usually necessary. Combinations of low-intensity treatments with venetoclax and potent FLT3 inhibitors are feasible and have shown encouraging outcomes. Dose adjustments are essential to reduce treatment-related myelosuppression.

Keywords:  AML; Acute myeloid leukemia; FLT3; Low-intensity treatment; Venetoclax

DOI:  https://doi.org/10.1007/s11912-025-01709-8
Genes Dev. 2025 Jul 28.

Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness.

Aishwarya S Pawar, Patrick Somers, Aleena Alex, Jason Grana, Victoria K Feist, Subin S George, Sapana S Jalnapurkar, Charles Antony, Roman Verner, Sanese K White-Brown, Mohit Khera, María Saraí Mendoza-Figueroa, Kathy Fange Liu, Jennifer J D Morrissette, Sandeep Gurbuxani, Vikram R Paralkar.

  Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). PHF6 mutations are associated with poorer outcomes, whereas PHIP was recently identified as the most common selective mutation in Black patients with AML. Here, we show that Phf6 knockout converts Flt3-ITD-driven mouse chronic myelomonocytic leukemia (CMML) into AML with reduced survival. Using cell line models, we show that PHF6 is a transcriptional repressor that suppresses a limited stemness gene network and that PHF6 missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or nonfunctional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that PHIP loss phenocopies PHF6 loss and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia mutated proteins, into a common functional complex that suppresses AML stemness.

Keywords:  chromatin; leukemia; myeloid; stemness

DOI:  https://doi.org/10.1101/gad.352602.125
Blood Rev. 2025 Jul 25. pii: S0268-960X(25)00068-2. [Epub ahead of print] 101323

Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.

Ayman Mohammad, John Mascarenhas, Bridget K Marcellino, Daniel I Nathan.

  Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.

Keywords:  Clinical trials; Clonal cytopenia of undetermined significance; Clonal hematopoiesis; Inflammation

DOI:  https://doi.org/10.1016/j.blre.2025.101323
Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]

Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.

Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.

Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.

DOI: https://doi.org/10.1182/blood.2024027822
Cancer Discov. 2025 Aug 04.

ALKBH1 drives tumorigenesis and drug resistance via tRNA decoding reprogramming and codon-biased translation.

Chao Shen, Yuan Che, Keren Zhou, Kitty Wang, Wei Li, Diyuan Xue, Tong Wu, Lu Yang, Meiling Chen, Yue Sheng, Chengwan Zhang, Sean Robinson, Huiying Chen, Lillian Sau, Zhenhua Chen, Mark Wunderlich, Li Han, Tingting Tang, Ying Qing, Dong Wu, Miao Sun, Keith Leung, Katarzyna Dąbrowska, Patrick Pirrotte, Yueh-Chiang Hu, Lucy Y Ghoda, Bin Zhang, James C Mulloy, Minjie Wei, Guido Marcucci, Chuan He, Xiaolan Deng, Jianjun Chen.

Cancer cells utilize codon-biased translation to fuel tumorigenesis and drug resistance, but underlying mechanisms remain poorly understood. Here, we show ALKBH1 is overexpressed in acute myeloid leukemia (AML) and essential for leukemia stem/initiating cell (LSC/LIC) self-renewal and AML development/maintenance, whereas dispensable for normal hematopoiesis. ALKBH1 enhances mitochondrial assembly/function and oxidative phosphorylation (OXPHOS), crucial for AML survival/proliferation and resistance to venetoclax, a potent BCL2 inhibitor and widely-used first-line targeted therapy for AML in clinic. Mechanistically, ALKBH1 catalyzes 5-formylcytosine (f5C) at tRNA wobble positions, reprograming decoding and facilitating codon-biased translation, a mechanism we term "Epitranslatomic Midas touch", which in turn drives leukemogenesis and drug resistance by promoting synthesis of key oncogenic proteins like WDR43. Targeting ALKBH1, particularly together with venetoclax, exhibited potent anti-leukemia efficacy in preclinical models with favorable safety profiles. Collectively, our findings elucidate ALKBH1's pivotal role in codon-biased translation and tumorigenesis, and propose a novel therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1043
Clin Immunol. 2025 Jul 23. pii: S1521-6616(25)00148-2. [Epub ahead of print]280 110573

A specific bone marrow cytokine pattern in de novo acute myeloid leukemia.

Noémie Ravalet, Hélène Guermouche, Pierre Hirsch, Frédéric Picou, Vincent Flament, Caroline Deswarte, Amélie Foucault, Jenny Beaud, Emmanuelle Rault, Emeline Saindoy, Sébastien Lachot, Mara Memoli, Nawa Hachem, Jean-Alain Martignoles, Valérie Gissot, Ludovic Suner, Emmanuel Gyan, Ollivier Legrand, Olivier Hérault, François Delhommeau.

  Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic cancers. Cytokines play an important role in the regulation of normal and pathologic hematopoiesis. A pro-inflammatory state, described in hematopoietic malignancies, may participate in clonal selection. To identify recurrent cytokine patterns according to AML ontogenic subtypes, we quantified the concentration of 49 cytokines in the bone marrow (BM) plasma from 124 patients with AML or myelodysplastic syndrome (MDS), and from 94 healthy volunteers. We confirmed a pro-inflammatory profile in MDS and AML, with increased concentrations of CXCL8, CXCL10 and IL-6. Only a few cytokines varied when comparing AML to MDS. De novo AML subtypes carry a specific cytokine pattern dominated by the increase in CLEC11A concentrations and the decrease in FLT3 ligand concentrations. These cytokines could participate in clonal selection in this subtype of AML while being less critical in the other AMLs - i.e. secondary-like or TP53-mutated subtypes.

Keywords:  AML ontogeny; CLEC11A; FLT3L; bone marrow cytokines

DOI:  https://doi.org/10.1016/j.clim.2025.110573
Blood. 2025 Jul 30. pii: blood.2025028730. [Epub ahead of print]

Disease risk but not remission status determines transplant outcomes in AML: long-term outcomes of the ASAP trial.

Matthias Stelljes, Jan Moritz Middeke, Gesine Bug, Eva Maria Wagner-Drouet, Lutz P Mueller, Christoph Schmid, Stefan W Krause, Wolfgang Andreas Bethge, Edgar Jost, Uwe Platzbecker, Stefan Klein, Judith Niederland, Martin Kaufmann, Kerstin Schäfer-Eckart, Henning Baldauf, Friedrich Stölzel, Sarah Trost, Christoph Röllig, Malte von Bonin, Katharina Egger-Heidrich, Desiree Kunadt, Björn Steffen, Beate Hauptrock, Christoph Schliemann, Katja Sockel, Fabian Lang, Oliver Kriege, Judith Schaffrath, Christian Reicherts, Wolfgang E Berdel, Hubert Serve, Gerhard Ehninger, Alexander H Schmidt, Jan-Henrik Mikesch, Martin Bornhäuser, Johannes Schetelig.

Attempting to induce a complete remission (CR) prior to allogeneic hematopoietic cell transplantation (alloHCT) is current practice in patients with AML. A benefit of remission induction prior to alloHCT, however, has never been proven in a prospective trial. Potent conditioning regimens exist which allow for successful alloHCT in patients with active AML. Therefore, the ASAP trial was conducted to test remission induction by salvage chemotherapy prior to alloHCT against immediate transplantation after intensified conditioning. In total 281 patients with AML with poor response after first induction or untreated first relapse were randomized 1:1 to remission induction (RIST) with high-dose cytarabine plus mitoxantrone versus immediate alloHCT with sequential conditioning after non-intensive disease control measures (DisC) preferentially watchful waiting only. Overall survival (OS) at 5 years from randomization analyzed according to ITT was 46.1% for DisC versus 47.5% for RIST (p=0.82). In multivariable Cox regression analysis, genetic AML risk according to ELN (p<0.0001), age (p=0.001) and comorbidities (p=0.046) predicted survival, but not treatment arm (HR 1.08 for DisC versus RIST, p=0.67). In conclusion, long-term follow-up of the ASAP trial showed no survival advantage for standard salvage chemotherapy prior to alloHCT as opposed to immediate alloHCT. The trial results question the general concept of remission induction with intensive standard salvage therapy prior to alloHCT for all patients, since immediate alloHCT may reduce time in hospital and health care expenses. Well tolerable novel bridging therapies and post-transplant maintenance with targeted drugs are urgently warranted, especially for adverse-risk AML, to improve outcome after alloHCT. NCT02461537.

DOI: https://doi.org/10.1182/blood.2025028730
Blood Adv. 2025 Jul 28. pii: bloodadvances.2025016897. [Epub ahead of print]

Somatic Mutations in STAG2 Are Associated with Separated Megakaryocyte Nuclear Lobes in Myelodysplastic Syndromes.

Waihay J Wong, Rebecca L Zon, Christopher J Gibson, Caleb Ho, Olga Pozdnyakova, Donna S Neuberg, Elisabeth M Battinelli, Marlise R Luskin, Zuzana Tothova, Elizabeth A Morgan, Benjamin L Ebert.

Myelodysplastic syndrome (MDS) is driven by genetic mutations, but diagnosis relies on morphologic evaluation of bone marrow hematopoiesis. Only a small number of genetic abnormalities define specific bone marrow morphologic features in MDS, such as those harboring SF3B1 mutations and deletions of chromosome 5q. We hypothesized that additional genetic alterations are associated with specific dysplastic morphologic features in MDS. We assessed genetic-morphologic associations between commonly mutated genes and 10 morphologic features in a cohort of MDS bone marrows with a high degree of dysplasia. We replicated the association of SF3B1 mutations with ring sideroblasts and found that dysplastic megakaryocytes with separated nuclei were independently associated with STAG2 and/or ASXL1 mutations. In addition, STAG2 mutations were associated with abnormal myeloid nuclear segmentation and myeloid cell hypogranulation. These findings demonstrate that STAG2 and ASXL1 mutations are associated with specific morphologic abnormalities in MDS.

DOI: https://doi.org/10.1182/bloodadvances.2025016897
Blood Adv. 2025 Jul 30. pii: bloodadvances.2024014411. [Epub ahead of print]

Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions.

Laila Karra, Anna-Marie Finger, Lauren A Shechtman, Milana Krush, Rita Meng-Yao Huang, Morgan Prinz, Iliana Tennvooren, Kriti Bahl, Lisiena Hysienaj, Paulina Garcia-Gonzalez, Alexis J Combes, Hugo Gonzalez, Rafael Jose Argüello, Mathew H Spitzer, Jeroen P Roose.

Aberrantly elevated Ras signals, triggered by various distinct genetic mutations, are frequent features in myeloid leukemias. Normal hematopoiesis requires perpetual and balanced production of different blood cell lineages by multipotent hematopoietic stem cells (HSC). Stem- and progenitor- cells combine dormancy with proliferative drive and require finely tuned metabolism and protein translation rates. Due to the scarcity of stem cells, it has remained largely unknown how aberrantly elevated Ras signals may impact frequency, lineage potential, and quiescent metabolism in rare HSC. Using single cell proteomics and computational analyses, we characterized the effects of induced oncogenic mutant KRasG12D or overexpression of the Ras activator RasGRP1, compared to normal native hematopoiesis. The two Ras pathway lesions drive shared profound skewing towards and expansion of mature myeloid cells. The resolution of CyTOF unmasked opposing patterns for the HSC- and progenitor- compartments: Overexpression of RasGRP1 induced expansion of both subsets, whereas KRASG12D resulted in depletion. By combining spectral flow with SCENITHÔ, a method to quantitate protein translation as a proxy for metabolic state, we first corroborated that immature cells display low metabolic SCENITHÔ rates. Both RasGRP1 and KRASG12D drive elevated, mean SCENITHÔ signals in immature hematopoietic cells. However, RasGRP1-overexpressing stem cells retain a metabolically quiescent cell-fraction, whereas this fraction is incompatible with KRASG12D. Our temporal proteomics and metabolomics datasets provide mechanistic insights into altered hematopoiesis at single cell resolution and support the idea that the exact identity and duration of signals from Ras lesions has profound impacts on stem cell maintenance and lineage-potential.

DOI: https://doi.org/10.1182/bloodadvances.2024014411
Blood. 2025 Jul 29. pii: blood.2025028594. [Epub ahead of print]

Time to complete remission is an independent determinant of survival after intensive chemotherapy in AML.

Rithin Nedumannil, Michael Ashby, James P Rowland, Jacques A J Malherbe, Jared Fairbank, Kelli Gray, Sun Loo, Matthew Wright, John Reynolds, Devendra K Hiwase, Paula Marlton, Shaun A Fleming, Ashish Bajel, Andrew H Wei.

The purpose of this study was to explore and determine the optimal landmark for defining complete remission after intensive induction therapy that best correlates with long-term survival outcome among patients with newly diagnosed acute myeloid leukemia (AML).

DOI: https://doi.org/10.1182/blood.2025028594
Leuk Res. 2025 Jul 15. pii: S0145-2126(25)00279-6. [Epub ahead of print]157 107919

Avapritinib versus midostaurin or cladribine in advanced systemic mastocytosis: A retrospective real-world external control study.

Andreas Reiter, Jason Gotlib, Iván Álvarez-Twose, Deepti H Radia, Johannes Lübke, Priyanka J Bobbili, Aolin Wang, Saša Dimitrijević, Erin Sullivan, Juliana Schwaab, Ilene A Galinsky, Cecelia Perkins, Wolfgang R Sperr, Priya Sriskandarajah, Manasi Mohan, Teshawna Badu, Selvam R Sendhil, Mei Sheng Duh, Peter Valent, Daniel J DeAngelo.

  As there are no prospective randomized studies in patients with advanced systemic mastocytosis (AdvSM), we compared clinical outcomes between patients treated with avapritinib in the Phase I EXPLORER (NCT02561988) and Phase II PATHFINDER (NCT03580655) trials (N = 176) and patients treated with midostaurin (N = 99) or cladribine (N = 49) from a global, multi-center, retrospective, chart review study. Overall survival (OS) and duration of treatment (DOT) were compared between the cohorts using inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards models, and maximum reduction in serum tryptase levels was compared using adjusted generalized linear models. Median OS was not reached (95% confidence interval [CI]: 46.9 months, not estimable) for avapritinib, 28.6 (18.2, 44.6) months for midostaurin, and 23.4 (14.8, 40.6) months for cladribine. The avapritinib cohort had significantly longer OS compared to midostaurin (hazard ratio [HR] [95% CI]: 0.59 [0.36, 0.97]) and cladribine (0.32 [0.15, 0.67]), longer DOT (vs. midostaurin: 0.63 [0.41, 0.96]; vs. cladribine: 0.14 [0.09, 0.23]), and greater reduction in serum tryptase levels with mean difference [95% CI] vs. midostaurin of -72.8 % [-101.1 %, -44.6 %] and vs. cladribine of -25.0 % [-32.4 %, -17.7 %] (all p < 0.05). Results were similar in treatment-naïve (1 L) and previously treated (2 L+) patients; there was improved OS in 1 L avapritinib vs. 1 L midostaurin patients (HR: 0.14 [0.05, 0.42]; p < 0.001) and in 2 L+ avapritinib vs. 2 L+ cladribine patients (0.34 [0.16, 0.71]; p = 0.004). Together, we show that avapritinib treatment resulted in significantly improved OS, longer DOT, and greater reduction in serum tryptase levels compared to midostaurin or cladribine in real-world clinical practice.

Keywords:  Advanced systemic mastocytosis; Avapritinib; Cladribine; Duration of treatment; Midostaurin; Overall survival; Tryptase level

DOI:  https://doi.org/10.1016/j.leukres.2025.107919
Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]

Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.

Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.

Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.

DOI: https://doi.org/10.1182/blood.2024028079
Blood Cancer J. 2025 Jul 31. 15(1): 128

A clinico-genomic prognostic model for primary myelodysplastic neoplasm in Asia.

Harinder Gill, Rita Yim, Paul Lee, Xavier Cheng-Hong Tsai, Vivian W K Li, Garret M K Leung, Melissa Ooi, Tsz-Shing Hui, Radha Raghupathy, Lynn Chin, Lester Au, Qi Zhang, Tony K Y Wu, Carmen Y Y Lee, Wee-Joo Chng, Hwei-Fang Tien, Hsin-An Hou, Yok-Lam Kwong.

A personalized prognostic model that takes into account the unique molecular features of primary myelodysplastic neoplasm (MDS) in Asia patients is lacking. Diagnostic clinicopathologic features, cytogenetic changes, and gene mutations of ethnic Asian patients with primary MDS were analyzed. Variables were evaluated for associations with overall survival (OS), leukemia-free survival (LFS), and time to progression to secondary AML (TTP-sAML). Prognostic scores were built as a weighted sum of prognostic variables for each patient. The cohort comprised 1225 patients, with at least one gene mutation identified in 1177 patients (96%). Genomic factors associated with inferior outcomes included monosomy 7, del(5q), and GNAS and TP53 mutations for OS; trisomy 19, del(5q), monosomy 7, and GNAS, PTPN11 and TP53 mutations for LFS; and i(17q), del(5q), and NPM1, NRAS, GNAS, IDH2, SF3B1 and RUNX1 mutations for TTP-sAML. The Asian Prognostic Scoring System (APSS) was determined, stratifying patients into six prognostic risk categories. The APSS, compared with the International Prognostic Scoring System molecular (IPSS-M), showed superior concordance indices (C-indices) for OS (0.73 versus 0.57), LFS (0.72 versus 0.59), and TTP-sAML (0.75 versus 0.65) for this Asian cohort. In conclusion, the APSS enhanced prognostication of primary MDS in Asia.

DOI: https://doi.org/10.1038/s41408-025-01339-0
Leukemia. 2025 Jul 25.

MDM4 overexpression alleviates developmental and hematopoietic defects in Fancg deficient mice.

Maeva Loock, Carèle Fédronie, Carine Torset, Lucie Hernandez, Emmanuelle Latour, Samuel Quentin, Nathalie Gachard, Julie Lefrançois, Loïc Maillard, Francina Langa Vives, Véronique Parietti, Marie-Laure Arcangeli, Camille Lobry, Jean Soulier, Olivier Bluteau, Dominique Bluteau.

DOI: https://doi.org/10.1038/s41375-025-02692-6
Blood. 2025 Jul 25. pii: blood.2024027125. [Epub ahead of print]

HiJAKing the Hematopoietic System: A Low-Frequency JAK2V617F Clone Drives Myeloproliferative Neoplasm Pathology.

Dennis M Bonal, Alissa Oakes, Anna Chorzalska, Makayla Pardo, Max Petersen, Michael Yeh Clarke, Seo-Ho Lee, Adam J Olszewski, Diana Olguta Treaba, John L Reagan, Mark S Dooner, John Morgan, Paul Bertone, Ting Zhao, Wentian Yang, Corey E Ventetuolo, Gabriela S Hobbs, Joslyn Mills, Patrycja M Dubielecka.

JAK2V617F is one of the most common mutations in clonal hematopoiesis of indeterminate potential (CHIP) and a major driver of myeloproliferative neoplasms (MPN). To determine the impact of a low-frequency of JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine MPN model, where the whole BM transplantation (BMT) was performed using CD45.2 5.0x106 JAK2V617F donor cells into unconditioned CD45.1 recipient mice. BMT recipients developed a polycythemia vera (PV)-like phenotype (elevated hematocrit and leukocytosis) with a 2.7% average donor cell chimerism in peripheral blood. Eight months post-BMT, RNA-seq analysis of the BM sorted according to CD45.1/CD45.2 expression, showed significant upregulation of early erythroblast- and myeloid cell-specific transcripts, as well as downregulation of lymphoid transcripts in donor-derived cells compared to controls. Surprisingly, recipient-derived cells also showed upregulation of myeloid- and erythroblast-related transcripts, indicating a skewing of the non-JAK2V617F carrying recipient hematopoietic system towards an MPN-like phenotype. In addition, RNA-seq analysis of the BM stroma from JAK2V617F BMT recipients indicated significant loss of osteo-mesenchymal transcripts. Consistently, micro-CT imaging indicated loss of trabecular bone. In sum, our results indicate that the low frequency MPN-driving cells in unconditioned recipients not only impact hematopoiesis-supporting stroma but profoundly influences unmutated cells, uniquely altering their transcriptomic and phenotypic profiles. These observations are challenging our current understanding of etiology and therapeutic approaches to MPNs and other CHIP-associated diseases.

DOI: https://doi.org/10.1182/blood.2024027125
Blood Adv. 2025 Jul 28. pii: bloodadvances.2025016532. [Epub ahead of print]

Cost-Effectiveness of Upfront vs. Delayed Allogeneic Hematopoietic Stem Cell Transplant for Intermediate Risk AML.

Abdulrahman Alhajahjeh, Kishan Patel, Nikolai A Podoltsev, Tariq Kewan, Jessica M Stempel, Lourdes M Mendez, Stuart E Seropian, Lohith Gowda, Scott F Huntington, Maximilian F Stahl, Amer M Zeidan, George Goshua, Jan P Bewersdorf.

The ETAL-1 trial demonstrated that upfront allogeneic hematopoietic stem cell transplant (HSCT) improved disease-free survival (DFS) but not overall survival (OS) when compared to consolidation chemotherapy (CCT) followed by "delayed" HSCT on relapse in patients with intermediate-risk acute myeloid leukemia (AML). However, the health-economic implications of upfront HSCT compared to delayed HSCT are unknown. We developed a partitioned survival analysis model using derived survival data, probabilities of salvage treatments, utilities, and costs from the ETAL-1 trial and published literature. The primary outcome was the incremental net monetary benefit (INMB) from the perspective of the United States (US) and the United Kingdom (UK) healthcare systems, at all accepted willingness-to-pay (WTP) thresholds: $50,000-$150,000 per quality-adjusted life year (QALY) and £20,000-30,000/QALY, respectively. The respective INMBs favored upfront HSCT and were $497,100 (95% CI: $259,800 - $719,600) and £235,600 (95% CI: £166,800 - £298,500) at WTP thresholds of $150,000/QALY and £30,000/QALY. Across deterministic sensitivity analyses, no model input changed the conclusion that upfront HSCT is the cost-effective strategy in either jurisdiction. Probabilistic sensitivity analysis showed that upfront HSCT was cost-effective in 100% of iterations and was less costly and more effective (i.e., 'dominant') in over 90% of iterations in both healthcare systems. In conclusion, we conducted a partitioned survival analysis based on the ETAL-1 trial and showed that proceeding to HSCT in first remission is the cost-effective strategy in the care of intermediate-risk AML patients in both the US and the UK, as compared to delayed HSCT.

DOI: https://doi.org/10.1182/bloodadvances.2025016532
Blood Neoplasia. 2025 Aug;2(3): 100118

Replication of a GWAS signal near HLA-DQA2 with AML using a disease-only cohort and external population-based controls.

Rose Laflamme, Véronique Lisi, Josée Hébert, Guy Sauvageau, Sébastien Lemieux, Vincent-Philippe Lavallée, Guillaume Lettre.

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Genome-wide association studies have identified 4 common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent data sets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1865 controls from the population-based cohort CARTaGENE (CaG). Because genotypes were generated using different technologies in the 2 data sets (eg, low- vs high-coverage whole-genome sequencing), we applied stringent quality-control filters to minimize type 1 errors. We showed, using data reduction methods (eg, principal component analysis and uniform manifold approximation and projection), that our approach successfully integrated the Leucegene and CaG genetic data. We replicated the association between cytogenetically normal AML and rs3916765, a variant located near HLA-DQA2 (odds ratio, 1.96; 95% confidence interval, 1.26-3.06; P = .003). The effect size of this association was stronger when we restricted the analyses to patients with AML with NPM1 mutations (odds ratios of >2.25). We also found that rs3916765 is a whole-blood expression quantitative trait locus for HLA-DOB (P = 1.05 × 10-14) and HLA-DQA2 (P = 2.23 × 10-4). Our results confirm that a common genetic variant at the HLA locus associates with AML risk and the expression of HLA class 2 genes, providing new opportunities to improve disease prognosis and treatment.

DOI: https://doi.org/10.1016/j.bneo.2025.100118
Blood. 2025 Jul 29. pii: blood.2024028019. [Epub ahead of print]

Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression in patients.

Alastair Smith, Nicholas David Robert Denny, Catherine Chahrour, Kim Sharp, Marta Arachi, Ana Maria Dopico-Fernandez, Natalina Elliott, Joe Harman, Thomas Jackson, Huimin Geng, Owen Smith, Jonathan Bond, Irene Roberts, Ronald W W Stam, Nicholas Crump, James Davies, Anindita Roy, Thomas A Milne.

Genetic alterations alone cannot account for the diverse phenotypes of cancer cells. Even cancers with the same driver mutation show significant transcriptional heterogeneity and varied responses to therapy. However, the mechanisms underpinning this heterogeneity remain under-explored. Here, we find that novel enhancer usage is a common feature in acute lymphoblastic leukemia (ALL). In particular, KMT2A::AFF1 ALL, an aggressive leukemia with a poor prognosis and a low mutational burden, exhibits substantial transcriptional heterogeneity between individuals. Using single cell multiome analysis and extensive chromatin profiling, we reveal that much transcriptional heterogeneity in KMT2A::AFF1 ALL is driven by novel enhancer usage. By generating high resolution Micro Capture-C data in primary patient samples, we identify patient-specific enhancer activity at key oncogenes such as MEIS1 and RUNX2, driving high levels of expression of both oncogenes in a patient-specific manner. Overall, our data show that enhancer heterogeneity is highly prevalent in KMT2A::AFF1 ALL and may be a mechanism that drives transcriptional heterogeneity in cancer more generally.

DOI: https://doi.org/10.1182/blood.2024028019
Cell Rep. 2025 Jul 25. pii: S2211-1247(25)00846-0. [Epub ahead of print]44(8): 116075

SUGP1 loss drives SF3B1 hotspot mutant missplicing in cancer.

Peiqi Xing, Pedro Bak-Gordon, Jindou Xie, Jian Zhang, Zhaoqi Liu, James L Manley.

  SF3B1 is the most frequently mutated splicing factor in cancer. Such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs mechanistically remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulates mutant SF3B1-induced splicing dysregulation. Strikingly, our analysis reveals only two proteins whose knockdown or knockout reproduces this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulates almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduces ∼40% of these defects. However, we find that AQR knockdown causes significant SUGP1 missplicing and reduced SUGP1 levels, suggesting that AQR loss reproduces mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic SF3B1 mutations and highlights the fundamental role of SUGP1 in this process.

Keywords:  AQR; CP: Molecular biology; DDX42; DDX46; DHX15; SETX; SF3B1; SUGP1; cancer; mutations; splicing

DOI:  https://doi.org/10.1016/j.celrep.2025.116075
Cancer Metab. 2025 Jul 25. 13(1): 36

Pharmacological inhibition of Peroxisome Proliferation-Activated Receptor Delta (PPARδ) imparts selective leukemia cell death.

Yingying Yang, Ekaterina Parfenova, Nikolina Vrdoljak, Mark Minden, Jessica Luc, Andrew C Doxey, Paul A Spagnuolo.

   BACKGROUND: Acute myeloid leukemia (AML) is a devastating hematological malignancy with limited therapeutic options and poor survival outcomes. Therefore, the development of novel and selective anti-AML therapies is needed. 6-methoxydihydroavicine (6ME), a benzophenanthridine alkaloid, imparted selective AML cell death in vitro and in vivo. Mechanistically, 6ME inhibited fatty acid oxidation (FAO) by binding to and decreasing the activity of PPARδ, a transcription factor involved in FAO.
METHODS: AML cell lines and patient-derived cells were used to assess the activity of 6ME in vitro and in vivo. Computational methods, immunoblotting, and co-IP-HPLC analysis assessed the molecular target, and cellular consequence of 6ME activity.
RESULTS: 6ME induced cytotoxicity of AML cell lines (IC50: 1.0 ± 0.13 μM) and patient-derived cells while sparing normal hematopoietic cells. Mouse engraftment studies showed that 6ME (5 mg/kg, three times/week for 4 weeks) selectively reduced patient-derived AML cell engraftment without affecting hematopoietic cell engraftment or imparting toxicity. Mechanistically, 6ME bound to and inhibited PPARδ leading to downregulated FAO gene expression (i.e., CD36 and CPT2) and reduced fatty acid cellular uptake resulting in FAO inhibition.
CONCLUSION: Pharmacological inhibition of PPARδ with 6ME is a novel approach to inducing selective death in AML.

Keywords:  6-methoxydihydroavicine; Acute myeloid leukemia; Fatty acid oxidation; PPAR

DOI:  https://doi.org/10.1186/s40170-025-00402-5
iScience. 2025 Aug 15. 28(8): 113077

A molecular-based risk score for predicting leukemia-free survival in adult AML patients undergoing Allo-HSCT.

Shuang Li, Huixian Wu, Xiaoxia Hu, Fang Zhou, Xiong Ni, Yi Ding, Jiangbo Wan, Xiaorui Wang, Yu Cai, Jun Yang, Yin Tong, Huiying Qiu, Chongmei Huang, Kun Zhou, Liping Wan, Xianmin Song.

  Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the cornerstone of curative therapy for acute myeloid leukemia (AML), yet precise molecular prognostic tools are currently insufficient. This study developed a prognostic model, AML-PRSS, integrating genomic and clinical factors from 389 adult AML patients undergoing their first allo-HSCT between 2013 and 2021. Seven genetic mutations significantly associated with leukemia-free survival (LFS) were categorized as favorable (DNMT3A, CEBPA bZIP domain, NPM1 without FLT3-ITD or with FLT3-ITD plus tyrosine kinase inhibitors), unfavorable (NRAS and GATA2), and high-risk (TP53 and U2AF1). Multivariate analysis identified molecular risk, cytogenetic risk, pre-transplant disease status, age, and hematopoietic cell transplant-comorbidity index (HCT-CI) score as independent predictors of LFS. AML-PRSS stratified patients into four risk groups with stepwise increasing hazard of LFS failure. Validation in an independent multi-center cohort of 266 patients confirmed robust predictive accuracy, highlighting AML-PRSS as an effective tool for personalized prognostication and clinical decision-making.

Keywords:  Bioinformatics; Hematology

DOI:  https://doi.org/10.1016/j.isci.2025.113077
Blood Neoplasia. 2025 Aug;2(3): 100107

Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML.

Mengdan Liu, Ming Yan, Amanda G Davis, Samuel A Stoner, Edward D Ball, Dong-Er Zhang.

Acute myeloid leukemia (AML) is a blood cancer complicated by acquired drug resistance, disease relapse, and low overall survival rates. Combination therapies using multiple targeted inhibitors have been effective in treating patients with AML. However, combination treatments are limited by the number of usable targets and our ability to create rational pairings using complimentary molecular mechanisms. Here, we used a human kinase domain-targeted CRISPR screen to identify histone H3-associated protein (HASPIN) kinase as a significant, understudied dependency in AML. HASPIN depletion significantly reduced growth rate, induced a cell cycle arrest, and dysregulated transcription in AML. A proteomics data mining study characterized serine and arginine repeat enriched splicing factors (SR proteins) as a major category of HASPIN kinase substrates and highlighted the role of HASPIN as a splicing regulatory kinase. Accordingly, HASPIN depletion strongly dysregulated splicing in AML cells. HASPIN inhibitor CHR-6494 effectively reduced cell viability across AML subtypes while sparing healthy cells. Furthermore, a novel combination therapy consisting of CHR-6494 and B-cell lymphoma 2 (BCL-2) inhibitor venetoclax synergistically reduced AML cell viability and resensitized venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel therapeutic target for AML, underscores an underappreciated role of HASPIN in splicing regulation, and proposes a viable combination treatment for clinical testing.

DOI: https://doi.org/10.1016/j.bneo.2025.100107
Leuk Res. 2025 Jul 28. pii: S0145-2126(25)00284-X. [Epub ahead of print]157 107924

Menin inhibitors in KMT2A-rearranged leukemia: Mechanistic insights, clinical trial progress, and potential of combination therapies.

Xinyu Yang, Rui Huang.

  Leukemia driven by rearrangement of the Lysine Methyltransferase 2 A (KMT2A) gene, formerly known as mixed-lineage leukemia (MLL), is associated with poor prognosis due to the formation of oncogenic fusion proteins. Menin, a scaffold protein encoded by the MEN1 gene, plays a critical role in the pathogenesis of KMT2A-rearranged (KMT2A-r) leukemia. Targeting menin has emerged as a promising therapeutic strategy, leading to the development of several menin inhibitors, some of which have entered clinical trials. Notably, Revumenib has been approved for clinical use. However, resistance to menin inhibition is an increasing concern, necessitating alternative approaches. Combining menin inhibitors with other therapeutic strategies appears to enhance efficacy and mitigate resistance. This review summarizes recent advancements in menin inhibitor research for KMT2A-r leukemia, including mechanistic insights and clinical trial progress, while also exploring the potential of combination therapies. A deeper understanding of the mechanisms underlying menin inhibition and resistance is crucial for developing more effective treatments to improve patient outcomes.

Keywords:  KMT2A-r leukemia; combination therapy; menin inhibitor; resistance

DOI:  https://doi.org/10.1016/j.leukres.2025.107924
Br J Haematol. 2025 Jul 31.

Assessment of peripheral blood DNA methylation signatures as pharmacodynamic and predictive biomarkers during azacitidine therapy in juvenile myelomonocytic leukaemia: Results of the EWOG-MESRAT study.

Maximilian Schönung, Silvia Rathmann, Senthilkumar Ramamoorthy, Dirk Lebrecht, Thomas Klingebiel, Franco Locatelli, Karsten Nysom, Claudia Rossig, Jan Starý, Marco Zecca, Meera Patturajan, Miriam Erlacher, Brigitte Strahm, Charlotte M Niemeyer, Daniel B Lipka, Christian Flotho.

  EWOG-MESRAT (European Working Group-Methylation Signatures and Response to Azacitidine Therapy; DRKS00007185) is an investigator-initiated trial that studied EPIC array-based DNA methylation patterns and next generation sequencing (NGS)-based variant allele frequencies (VAFs) of driver mutations in peripheral blood (PB) and bone marrow (BM) of 11 patients with newly diagnosed juvenile myelomonocytic leukaemia (JMML) during therapy with azacitidine. We demonstrate that the pharmacodynamic activity of azacitidine can efficiently be monitored in PB and BM. DNA methylation subgroup classification was linked to clinical response after three cycles of azacitidine and found to be conserved between PB and BM in all patients. In contrast, neither changes in VAFs nor changes in DNA methylation patterns during the course of therapy correlated with therapy outcome among the 11 study patients. This work thus supports the value of DNA methylation subgroup classification from PB samples for response prediction of single-agent azacitidine in patients with JMML.

Keywords:  DNA methylation; JMML; azacitidine; epigenetics

DOI:  https://doi.org/10.1111/bjh.70046
Stem Cell Reports. 2025 Jul 28. pii: S2213-6711(25)00200-0. [Epub ahead of print] 102596

Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency.

Ali Abdelfattah, Ahmad Habib, Leigh-Anne Thomas, Juan Bautista Menendez-Gonzalez, Alhomidi Almotiri, Hind Alqahtani, Hannah Lawson, Sarab Taha, Millie Steadman, Radhika Athalye, Alex Gibbs, Hamed Alzahrani, Ali Alshahrani, Alice Cato, Peter Giles, Alex Tonks, Ashleigh S Boyd, Kamil R Kranc, Neil P Rodrigues.

  Clinical GATA2 haploinsufficiency results in immunodeficiency that evolves to leukemia. How GATA2 haploinsufficiency disrupts the functionality of hematopoietic stem/progenitor cells (HSCs/HSPCs) to facilitate pre-leukemia development is poorly defined. Using a hematopoietic-specific conditional mouse model of Gata2 haploinsufficiency, we identified pervasive defects in HSPC differentiation in young adult Gata2 haploinsufficient mice and perturbed HSC self-renewal following transplantation. These alterations aligned with deregulated global DNA damage responses and inflammatory cell signaling from Gata2 haploinsufficient HSCs. We also discovered genetic interplay between Gata2 and Asxl1, a secondary mutation leading to leukemia in GATA2 deficiency syndromes. HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice were hyperproliferative, functionally compromised after transplantation, and displayed a broad pre-leukemia transcriptomic program. Thus, Gata2 haploinsufficiency triggers HSC genomic instability. Our data further suggest that secondary mutations like ASXL1 exploit this impaired HSC genomic integrity to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.

Keywords:  DNA damage response; GATA2 haploinsufficiency; hematopoietic stem cells; inflammation; pre-leukemia

DOI:  https://doi.org/10.1016/j.stemcr.2025.102596
Blood. 2025 Jul 29. pii: blood.2025029691. [Epub ahead of print]

A clinical guide to TP53 mutations in myeloid neoplasms.

Samuel Urrutia, Terrence N Wong, Daniel C Link.

TP53 mutations are found in 10-15% of myeloid neoplasms and are one of its most important prognostic factors. Emerging data show that TP53 mutational allele status is a key determinant of clinical outcomes, with multi-hit TP53 mutant myeloid neoplasms having a very poor prognosis. Significant differences exist among the methods used in clinical and research settings to assess TP53 mutational status, leading to variability in reported patient characteristics, response to therapy, and survival. Indeed, differences in the criteria used to define TP53 mutational states among professional societies and in landmark research studies have led to confusion, suboptimal clinical testing, and variability in therapy recommendations. We review the methods used to assess for TP53 mutational allele status and provide recommendations, based on clinically available testing, for the accurate evaluation of TP53 gene mutations in myeloid neoplasms. Hotspot mutations represent ~35% of all TP53 missense mutations in myeloid neoplasms. There is evidence that these hotspot mutations may have dominant-negative or gain-of function properties. Here, we review this evidence and discuss the potential impact of TP53 mutation identity on patient outcomes and clinical management.

DOI: https://doi.org/10.1182/blood.2025029691
Leuk Res. 2025 Jul 22. pii: S0145-2126(25)00280-2. [Epub ahead of print]156 107920

Outcomes with intensive chemotherapy, compared to hypomethylating agent + venetoclax, in patients with intermediate and adverse risk acute myeloid leukemia.

Todd William Mudd, Kendall Diebold, Katherine Parks, Maris Hardee, Jay Jarodiya, Manuel Espinoza-Gutarra, Pankit Vachhani, Kimo Bachiashvili, Sravanti Rangaraju, Razan Mohty, Ravi Bhatia, Omer Jamy.



Keywords:  Acute Myeloid Leukemia; Adverse-Risk; Hypomethylating Agent; Intensive Chemotherapy; Intermediate-Risk; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2025.107920
Blood Neoplasia. 2025 Aug;2(3): 100110

Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia.

Martin Hutchings, Koorosh Korfi, Pau Montesinos, Armando Santoro, Hsin-An Hou, Pilar Martinez-Sanchez, Susana Vives, Sara Galimberti, Tsai-Yun Chen, Marco Frigeni, Sylvain Garciaz, Olga Salamero Garcia, Su-Peng Yeh, Karen Yee, Jordi Esteve, Ashish Bajel, Shaun Fleming, Anne Catherine Bretz, Jan Attig, Min Sun, Sina Nassiri, Tobias Rutishauser, Christian Klein, Y May Ma, Gabriel Schnetzler, Stephanie Vauleon, Huixin Yu, Teresa Barata, Muriel Richard, Silke Simon, Heather Hinton, Nino Keshelava, Marion Subklewe.

A novel T-cell bispecific antibody (TCB), RO7283420, engaging CD3 and the HLA-A2-Wilms tumor protein 1 complex, was evaluated in this phase 1 study to characterize safety and tolerability, determine the maximum tolerated dose (MTD), and recommend a phase 2 dose for patients with relapsed/refractory acute myeloid leukemia in 2 groups: hematologic (group I, n = 57) and molecular (group 2, n = 5) relapse. In group I, 51 received RO7283420 intravenously (IV) and 6 subcutaneously. The IV doses ranged from 0.15-4 mg (flat; n = 13), 3-18 mg (step-up; n = 34) every 3 weeks, or 9 mg weekly (step-up; n = 4). The MTD was 1/3/12 mg every 3 weeks. The most frequent adverse event in the overall population was cytokine release syndrome (61.3%) with grade ≥3 recorded in 9.7% of patients. Twelve dose-limiting toxicities were reported in 11 patients and 12 (19.4%) grade 5 adverse events, including 1 hemophagocytic lymphohistiocytosis case related to RO7283420. Among the 42 efficacy-evaluable IV patients in group I, 4.8% achieved complete remission (CR), and 2.4% achieved CR with incomplete hematologic recovery. RO7283420 induced pharmacodynamic changes in peripheral blood (PB) at doses ≥1 mg, including significant T-cell activation and expansion in the PB and bone marrow (BM). Significant associations were found between blast reduction and baseline immunophenotype, including lower regulatory T cells and higher non-exhausted CD8+ T cells in BM. Although dose escalation was discontinued because of limited efficacy and lack of an exposure-BM response relationship, the observed pharmacodynamics underscore the promising potential of this class of TCBs targeting intracellular antigens. This trial was registered at www.clinicaltrials.gov as #NCT04580121.

DOI: https://doi.org/10.1016/j.bneo.2025.100110
Br J Haematol. 2025 Aug 01.

Bisantrene in combination with fludarabine and clofarabine as salvage therapy for adult patients with refractory or relapsed acute myeloid leukaemia (AML)-An open-label, phase I/II study.

Ivetta Danylesko, Avichai Shimoni, Abraham Avigdor, Meirav Kedmi, Irina Amitai, Noga Shem-Tov, Ronit Yerushalmi, Borje S Andersson, Arnon Nagler.

  Bisantrene (Bis), an anthracene derivative with topoisomerase-II inhibitory activity and low cardiotoxicity, may enhance its efficacy when combined with nucleoside analogues such as clofarabine (Clo) and fludarabine (Flu) in preclinical acute myeloid leukaemia (AML) studies. We conducted a phase I/II open-label study (NCT04989335) to evaluate the safety and efficacy of Bis/Clo/Flu in relapsed/refractory AML. Twenty-one patients (median age: 47 years, 55% female) received Flu (10 mg/m2), Clo (30 mg/m2) and Bis (250 mg/m2) intravenously for 4 days. Sixteen had relapsed post-allogeneic stem cell transplantation, and six had extramedullary disease (EMD). Liver toxicity occurred in 10 patients but resolved. No significant cardiac toxicity was observed. Efficacy was assessable in 15 patients, while in six patients, it could not be evaluated due to early non-relapse mortality occurring within 30 days of treatment initiation, before the first post-treatment assessment. Six of the 15 patients responded: five achieved complete remission, and one with EMD achieved a partial remission, yielding a 40% response rate. Responses were transient, but six patients, including four undergoing second allo-HSCTs, proceeded to allo-HSCT within 1-3 months post-treatment. The Bis/Clo/Flu regimen demonstrated a tolerable safety profile and potential as a bridging therapy in high-risk, heavily pretreated AML.

Keywords:  acute myeloid leukaemia; chemotherapy: refractory/relapsed

DOI:  https://doi.org/10.1111/bjh.70035
Leukemia. 2025 Jul 28.

Transcriptomic landscape of CD8+ and CD4 + T-LGL leukemia revealed the distinct impact of STAT3 and STAT5B activating mutations.

Giulia Calabretto, Andrea Binatti, Antonella Teramo, Alessia Buratin, Gregorio Barilà, Vanessa Rebecca Gasparini, Cristina Vicenzetto, Enrico Gaffo, Elisa Rampazzo, Silvia Orsi, Elena Buson, Valentina Trimarco, Barbara Mariotti, Monica Facco, Flavia Bazzoni, Livio Trentin, Gianpietro Semenzato, Renato Zambello, Stefania Bortoluzzi.

The biological basis of the high clinical heterogeneity of T-LGL Leukemia (T-LGLL) is not completely understood and effective therapies for this disease are lacking. Through RNA-Sequencing of purified T-LGLs we reveal gene expression profiles and pathway dysregulations in the major patient subgroups, defined by CD8+ or CD4+ phenotype and STAT3/STAT5B mutational status. Overall, T-LGLL patients exhibited a marked transcriptome dysregulation compared to controls. This was more pronounced in the most symptomatic CD8 + STAT3-mutated patients, which emerged as a distinct biological entity, separated from the other disease subgroups. Particularly, CD8 + STAT3-mutated cases displayed extensive down-regulation of genes, ultimately resulting in the de-repression of proliferation and cell cycle pathways. Among genes up-regulated in CD8 + STAT3-mutated cases we found VCAM1, the transcriptional repressor EZH2 and the p53-regulator MDM2 proto-oncogene, as well as the leukemogenesis-associated PVT1 up-regulation, representing the first report of a long-non-coding RNA alterations in leukemic T-LGLs. The impact of STAT5B mutations on T-LGLs transcriptome was more limited and the overexpression of the PIM1 serine/threonine kinase proto-oncogene was identified as one of the most relevant features of STAT5B-mutated CD4 + T-LGLL. This study significantly advances our understanding of T-LGLL pathogenesis, uncovering new oncogenic mechanisms within the distinct molecular subtypes of the disease.

DOI: https://doi.org/10.1038/s41375-025-02708-1
Cell Rep. 2025 Jul 30. pii: S2211-1247(25)00858-7. [Epub ahead of print]44(8): 116087

Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.

Hong Zheng, Peng Zhao, Zhenya Tan, Wen-Mei Yu, Juwita Werner, Elliot Stieglitz, Christopher C Porter, Shanmuganathan Chandrakasan, Daniel S Wechsler, Simon Mendez-Ferrer, Cheng-Kui Qu.

  Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11E76K/+ mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8. Biological experiments confirm that S100a9/S100a8 confer a selective advantage to mutant stem cells through autocrine effects and facilitate immune evasion by recruiting and promoting immune-suppressive myeloid-derived suppressor cells in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impede leukemia development from Ptpn11E76K/+ mutant stem cells. These findings collectively suggest that JMML-initiating cells exploit innate immune and inflammatory mechanisms to establish clonal dominance.

Keywords:  CP: Cancer; CP: Immunology; JMML; PTPN11; S100a8; S100a9; hematopoietic stem cell; inflammation; innate immunity; leukemia-initiating cell

DOI:  https://doi.org/10.1016/j.celrep.2025.116087
Br J Haematol. 2025 Jul 29.

The importance of systemic inflammatory response measurements as pretransplant risk factors for outcome after allogeneic haematopoietic cell transplantation.

Hartmut Bertz, Jörg Sahlmann, Donald C McMillan, Claudia Wehr, Jesus Duque-Afonso, Kristina Maas-Bauer, Ralph Wäsch, Julia Nikolaychuk, Christine Greil, Jann Arends, Jürgen Finke, Robert Zeiser.

  Systemic inflammatory response (SIR) measures are known prognostic values in patients with solid tumours. Little is known about their impact in haematological diseases or allogeneic haematopoietic cell transplantation (alloHCT). Therefore, we evaluate the association of pretransplant inflammatory markers with the clinical outcome in a prospective analysis of alloHCT. We included 2201 consecutive patients undergoing their first alloHCT. At admission, C-reactive protein (CRP), serum albumin (sALB), a composite inflammatory score (modified Glasgow prognostic score, mGPS) and the body mass index (BMI) were recorded. These, the EBMT score and the HCT-specific comorbidity index (HCT-CI) were statistically analysed for overall/progression-free survival (OS/PFS), non-relapse mortality (NRM), relapse and graft-versus-host disease (GvHD). CRP was increased in 34.8%, 17% had a low sALB, 2.9% an increased (≥35 kg/m2) and 3% a very low BMI (<18.5 kg/m2). For mGPS, we observed score 1 (24%) and 2 (11%). A multivariable model explored mGPS 1 (SHR 1.301) and mGPS 2 (SHR 1.915) as significant risk factors (p < 0.001) for OS and for PFS (mGPS 1 (SHR 1.202); mGPS 2 (SHR 1.765)). Only mGPS 2 (HR 1.671; p < 0.001) revealed influence on NRM. Pretransplant SIR markers and their combination (mGPS) displayed a highly significant association with clinical outcome, possibly enriching present alloHCT risk scores.

Keywords:  allogeneic haematopoietic stem cell transplantation; modified Glasgow prognostic score; outcome; risk factors; systemic inflammation response measures

DOI:  https://doi.org/10.1111/bjh.70049
Blood Adv. 2025 Jul 30. pii: bloodadvances.2025016260. [Epub ahead of print]

Pilot study of an inpatient physical activity intervention for older adults treated intensively for acute myeloid leukemia.

Heidi D Klepin, Janet A Tooze, W Jack Rejeski, Shannon L Mihalko, Timothy S Pardee, Leslie R Ellis, Dianna S Howard, Wendy Demark-Wahnefried, Bayard L Powell, Stephen Kritchevsky.

Interventions to maintain physical function during treatment may improve outcomes for older adults with AML. We tested the feasibility of a randomized physical activity (PA) intervention among older adults (aged ≥60y) receiving induction chemotherapy for newly diagnosed AML and estimated the effect on physical function, quality of life (QOL) and symptoms. Intervention participants were offered PA sessions five days/week tailored daily to symptoms during the induction hospitalization coupled with weekly behavioral counseling sessions that continued monthly by phone for 6 months. The primary outcome was feasibility (recruitment, retention, participation). The key secondary outcome of interest was the Short Physical Performance Battery (SPPB). SPPB was assessed at baseline, weekly during hospitalization, 3 months, and 6 months. Among 96 eligible patients 70 enrolled (mean age 72.1±6.3 years, range 60 to 88). Primary feasibility outcomes were met with a recruitment rate of 72%, adherence 74% and average participation of 3 sessions/week. Among survivors the retention was 96% and 95% at 3 (N=51/53) and 6 (N=42/44) months. In exploratory analyses, SPPB scores were maintained or improved in 38% of intervention participants vs. 25% of controls at end induction (N=66, p=0.21). There were no differences between groups on QOL or symptoms. A PA intervention with behavioral counseling during induction was feasible for older adults receiving intensive therapy for AML. ClinicalTrials.gov ID number NCT01519596.

DOI: https://doi.org/10.1182/bloodadvances.2025016260
Eur J Med Chem. 2025 Jul 21. pii: S0223-5234(25)00753-6. [Epub ahead of print]298 117988

Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML through MCL-1 co-targeting.

Maoqian Zhang, Shuyun Wu, Menghui Liu, Haozhe Li, Luyao Wang, Feimeng Duan, Rui Han, Chenxiao Shan, Zequn Jiang, Junzhuo Liao, Yongmin Zhang, Wei Li, Bo Wang.

SHP2, an oncogenic phosphatase pivotal in RAS-MAPK, PI3K-AKT, and JAK-STAT signaling, represents a compelling therapeutic target in malignancies driven by its hyperactivation. While allosteric inhibitors like SHP099 have overcome historical challenges of orthosteric agents by stabilizing SHP2's autoinhibited conformation, opportunities remain to enhance potency, selectivity, and clinical utility. Here, we report a structure-guided expansion strategy leveraging detailed profiling of the tunnel-shaped allosteric pocket to design next-generation inhibitors. Systematic optimization of a pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one scaffold yielded compounds B1 and B8, which exhibit nanomolar enzymatic inhibition (IC50 = 39 and 15 nM), acceptable pharmacokinetics, and potential oral bioavailability. Strikingly, B8 demonstrated profound synergy with MCL-1 inhibitor VU661013 in acute myeloid leukemia (AML) models, a novel discovery underscoring the therapeutic potential of dual SHP2/MCL-1 targeting. Our work not only advances the rational design of oral allosteric SHP2 inhibitors but also unveils a critical vulnerability in AML through SHP2-MCL-1 co-targeting, offering a roadmap for combinatorial regimens to improve outcomes in high-risk cancers.

DOI: https://doi.org/10.1016/j.ejmech.2025.117988
Blood. 2025 Jul 29. pii: blood.2024028216. [Epub ahead of print]

Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome.

Paul Breillat, Francesco Carbone, Emilie Lereclus, Quentin Riller, Thibaut d'Izarny-Gargas, Celine Posseme, Marie Templé, Lin-Pierre Zhao, Marine Luka, Estibaliz Lazaro, Roderau Outh, Guillaume Le Guenno, Francois Lifermann, Yannick Dieudonné, Marie Berleur, Cédric Lenormand, Karl Balabanian, Thierry Weitten, Vivien Guillotin, Marie Kostine, Barbara Burroni, Adrien Bigot, Alexandra Audemard-Verger, Aldric Manuel, Antoine Dossier, Cécile Golden, Jean-Philippe Martellosio, Benoit Faucher, Benjamin De Sainte Marie, Nadine Magy-Bertrand, Valentin Lacombe, Stéphane Vinzio, Sylvie Grosleron, Léa Dionet, Pierre-Louis Tharaux, Darragh Duffy, Mickaël Mathieu Ménager, Nicolas Dulphy, Olivier Kosmider, Benjamin Terrier.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic UBA1 mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections observed in VEXAS patients, we hypothesized that NK cell dysfunction contributes to this increased susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n=40), patients with autoinflammatory diseases without UBA1 mutations (n=22), and elderly gender-matched healthy controls (HCs) (n=16). Multiparameter phenotyping was performed using CyTOF, scRNAseq, whole blood stimulation assays and in vitro NK cell cytotoxic assay. Peripheral NK cells in VEXAS were quantitatively and qualitatively impaired. Mass cytometry revealed reduced frequencies of mature cytotoxic CD56dim NK cells and an expansion of the CD56high CD16dim subset. NK cells exhibited features of exhaustion, including increased PD-1 expression, and reduced levels of cytotoxic markers such as NKp46 and CD8α. scRNAseq analysis showed decreased signatures of cytotoxicity and IL-2 and IFN-γ production, alongside increased inflammatory signatures. Whole blood stimulation assays confirmed impaired IL-2, IFN-γ, and granzyme B production following TLR3, TLR4, and TLR7/TLR8 agonist stimulation. Extended NK phenotyping by flow cytometry confirmed reduced activating receptors' expression and impaired IFN-γ production in VEXAS. Moreover, in vitro UBA1 inhibitors impaired NK cell cytotoxic capacity and promote cell death. Finally, reduced NK cell frequencies were independently associated with an increased risk of severe infections. These findings suggest that NK cell dysfunction in VEXAS syndrome contributes to increased susceptibility to severe infections.

DOI: https://doi.org/10.1182/blood.2024028216
Nat Metab. 2025 Jul 29.

Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.

Aparna D Rao, Ling Cai, Marelize Snyman, Rachel E Walsdorf, Xiangyi Li, Sophia N Wix, Gabrielle Gard, Ariel B Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G Zacharias, Kristen A Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P Mathews, Sean J Morrison, Ralph J DeBerardinis, Jennifer G Gill.

Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.

DOI: https://doi.org/10.1038/s42255-025-01338-2
Leukemia. 2025 Aug 01.

Evaluating a predictive model of tyrosine kinase inhibitor therapy failure in a European-type cohort: a step towards population-specific tools.

Sylvain Moinard, Benjamin Lebecque, Tom Lachaise, Hyacinthe Johnson-Ansah, Charlotte Doublet, Gabrielle Roth-Guepin, Françoise Rigal-Huguet, Lydia Roy, Anne Parry, Mathieu Meunier, Amélie Penot, Laurence Legros, Vanessa Pante, Martine Escoffre-Barbe, Philippe Rousselot, Guillaume Denis, Hélène Monjanel, Dalil Hamroun, Abdessattar Khlaifia, Joévin Besombes, Bruno Pereira, Céline Bourgne, Marc G Berger.

Predicting therapeutic failure in patients with chronic phase-chronic myeloid leukemia (CP-CML) treated with tyrosine kinase inhibitors (TKI) remains a major challenge for personalized care management. The Sokal and EUTOS long-term survival scores were designed to predict CML-related mortality, but are also used to guide therapeutic choices, despite their poor performance for this purpose. A recent study proposed a refined predictive model of therapy failure specifically tailored for patients treated with imatinib and second-generation TKIs that showed promising results in a Chinese cohort. The present study evaluated the performance and applicability of this predictive model in a real-world, multicenter cohort from the French CML Observatory. The key differences identified between the Chinese and French cohorts (age, baseline hemoglobin levels, and treatment regimens) likely influenced the model performance. Specifically, the new model did not allow for discriminating risk groups effectively in the French cohort. However, the model reconstruction using this cohort identified other predictive variables (sex, leukocytosis, comorbidities, high-risk additional chromosomal abnormalities) that better stratified patients at risk of therapy failure. Our findings highlight the influence of demographic and clinical differences on predictive models and emphasize the need for local or population-specific tools to optimize risk stratification and therapeutic decision-making in CP-CML.

DOI: https://doi.org/10.1038/s41375-025-02703-6