bims-tremyl 2026-09-13 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–09–13
thirteen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Haematopoietic stem cell fitness mechanisms.
Prognostic impact of age and MDS-associated mutations in NPM1-mutated AML.
Comparison of GvHD prophylaxis regimens based on in vivo T-cell depletion (ATG vs. alemtuzumab) in patients with AML undergoing allo-HCT from unrelated donors with intermediate transplant conditioning intensity protocols: a registry study on behalf of the EBMT acute leukemia working party.
Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.
Rare Hematopoietic Stem Cells resilient to infection-induced stress sense yet withstand inflammation.
Mutational Landscape and Clonal Dynamics in AML Undergoing PTCy Hematopoietic Cell Transplantation.
LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.
Estimated pulse wave velocity as a marker of major adverse cardiovascular events in essential thrombocythaemia and polycythaemia vera.
A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.
Extensive and differential platinum chemotherapy mutagenesis in livers of children.
Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.
Managing thrombotic risk in myeloproliferative disorders.
Berberine, a natural molecular glue degrader, overcomes CML resistance via TRIM28-mediated HIF1α ubiquitination and subsequent ferroptosis.

Exp Hematol. 2026 Sep 07. pii: S0301-472X(26)00538-2. [Epub ahead of print] 105905

Haematopoietic stem cell fitness mechanisms.

Yavor Bozhilov, Hugo Vassort, Adam C Wilkinson.

  Haematopoietic stem cells (HSCs) are important for human health and clinical therapy. A heterogenous pool of HSCs sustain blood production through life by balancing self-renewal and multilineage differentiation. Aging is associated with a decline in the function of the HSC pool and haematopoietic perturbations. Additionally, aging correlates with clonal haematopoiesis, driven by the accumulation of genetic mutations in this long-lived cell population that can lead to altered cell function and ultimately to leukemic transformation. Alongside their natural role in sustaining haematopoiesis, healthy HSCs are also used clinically for their regenerative capacity in stem cell transplantation, where they reconstitute the entire adult blood system and can cure a range of blood disorders. Within these contexts, the term fitness is regularly used but often poorly defined. In this perspective, we summarise two distinct types of HSC fitness, clonal fitness and stem cell fitness. We go on to introduce mechanisms known to shape each and discuss the therapeutic implications for modulating HSC fitness mechanisms. TEASER ABSTRACT: This Perspective discusses two types of hematopoietic stem cell fitness, clonal fitness and stem cell fitness, and summarise mechanisms known to shape each and their therapeutic implications.

Keywords:  Hematopoietic stem cell; clonal fitness; clonal hematopoiesis; stem cell fitness

DOI:  https://doi.org/10.1016/j.exphem.2026.105905
Blood Neoplasia. 2026 Nov;3(4): 100272

Prognostic impact of age and MDS-associated mutations in NPM1-mutated AML.

Vivian M Liu, Megan Othus, Jasmine Naru, Rhonda E Ries, Era L Pogosova-Agadjanyan, Frederick R Appelbaum, Thomas R Chauncey, Eliana Dietrich, Harry P Erba, John E Godwin, Matthew P Fitzgibbon, Min Fang, Stanley C Lee, Anna Moseley, Mary-Elizabeth Percival, Guangrong Qin, Jerald P Radich, Suravi Raychaudhuri, Cheryl L Willman, Soheil Meshinchi, Derek L Stirewalt.

Nucleophosmin-1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML) and is generally associated with favorable prognosis. However, the impact of myelodysplastic syndrome-associated mutations (MDSm+) on patient outcomes within this subgroup remains uncertain. We retrospectively analyzed 271 patients with NPM1-mutated AML from 3 independent cohorts (SWOG, Fred Hutch, and Beat AML) to assess the prognostic significance of MDSm+ and its interaction with age. MDSm+ occurred in 17% of patients, most commonly involving SRSF2 and SF3B1. Although MDSm+ was associated with inferior overall survival (OS) compared with MDSm- in European LeukemiaNet (ELN) 2022 favorable-risk patients (hazard ratio [HR], 2.0; P = .008), this effect was largely driven by worse outcomes in older patients (≥65 years) as older ELN2022 favorable-risk patients had poor OS regardless of the presence of MDSm+ compared with younger patients. After stratification of patients by age, there was not a significant difference between MDSm+ and MDSm- in either younger patients (HR, 0.99; P = .98) or older patients (HR, 1.42; P = .33). These findings indicate that MDSm+ in NPM1 + AML is not independently associated with adverse risk after adjusting for age, and highlight the need for age-adjusted AML risk models.

DOI: https://doi.org/10.1016/j.bneo.2026.100272
Bone Marrow Transplant. 2026 Sep 10.

Comparison of GvHD prophylaxis regimens based on in vivo T-cell depletion (ATG vs. alemtuzumab) in patients with AML undergoing allo-HCT from unrelated donors with intermediate transplant conditioning intensity protocols: a registry study on behalf of the EBMT acute leukemia working party.

Jesús Duque-Afonso, Jürgen Finke, Thibeault Ferhat-Berland, Jacques-Emmanuel Galimard, Francesca Kinsella, Deborah Richardson, Friedrich Stölzel, Eleni Tholouli, Caroline Besley, Matthias Eder, Emma Nicholson, Robert Zeiser, Adrian Bloor, Charles Crawley, Katherine Clesham, Jennifer Byrne, Patrick Medd, Elisa Sala, Caroline Pabst, Jan Vydra, Eva Maria Wagner-Drouet, Alain Gadisseur, Alexandros Spyridonidis, Eolia Brissot, Arnon Nagler, Mohamad Mohty, Fabio Ciceri.

Allogeneic hematopoietic cell transplantation is a potentially curative therapy for acute myeloid leukemia (AML), but its success is limited by graft-versus-host disease (GvHD). Optimal in vivo T-cell depletion strategies for GvHD prophylaxis given with conditioning regimens remain under investigation. We compared antithymocyte globulin (ATG) and alemtuzumab as GvHD prophylaxis in adult AML patients in complete remission (CR1/CR2) undergoing allogeneic cell transplantation from unrelated-donors conditioned with intermediate-intensity regimens. From the EBMT registry, 1545 patients were identified (710 ATG; 835 alemtuzumab). Patients receiving ATG were slightly older and had higher comorbidity scores, but groups were otherwise comparable. At 3 years, ATG was associated with superior overall survival (58.3% vs. 50.4%, p = 0.03) and leukemia-free survival (52.1% vs. 45.7%, p = 0.014). ATG recipients also demonstrated significantly lower relapse incidence (21.9% vs. 28.1%, p = 0.006), while non-relapse mortality remained similar between groups (26% vs. 26.3%, p = 0.46). Although ATG was associated with a higher incidence of acute GvHD, chronic GvHD rates did not differ significantly. In summary, for AML patients in complete remission receiving intermediate-intensity conditioning, ATG improved long-term survival and reduced relapse risk compared with alemtuzumab, despite increased acute GvHD. These findings support ATG as an effective GvHD prophylactic option in this setting.

DOI: https://doi.org/10.1038/s41409-026-03016-7
Hemasphere. 2026 Sep;10(9): e70429

Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.

Ilaria S Pagani, Vaidehi Krishnan, John F Ouyang, Chung H Kok, BeiJun Chen, Kian Leong Lee, Cong M Pham, Paul Wang, Elyse Page, Phuong Dang, Verity A Saunders, Jane James, Kelly Lim, Stefano Mangiola, Yingnan Gao, Naranie Shanmuganathan, Agnes Yong, Susan Branford, Charles Chuah, David T Yeung, Deborah L White, Vignir G Helgason, Daniel Thomas, S Tiong Ong, Timothy P Hughes, David M Ross.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.

DOI: https://doi.org/10.1002/hem3.70429
Blood. 2026 Sep 09. pii: blood.2025032368. [Epub ahead of print]

Rare Hematopoietic Stem Cells resilient to infection-induced stress sense yet withstand inflammation.

Christiana Georgiou, Qi Liu, Federica Bruno, Cera Mai, Floriane Simonne Tissot, Xuanxuan Fan, Sara Gonzalez Anton, Flora Birch, Debangana Mukhopadhyay, Sarah J Kinston, Shirom Chabra, Célia Sergi, Nick van Gastel, Ilaria Malanchi, Nicola K Wilson, Ken R Duffy, Constandina Pospori, Andrew M Blagborough, Berthold Gottgens, Tiago C Luis, Cristina Lo Celso.

Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis as their progeny differentiate into all blood cell lineages. Homeostatic HSCs are mostly quiescent and only rarely divide, however their proliferation and differentiation rates can be modulated by external factors. Acute and chronic infections from a wide range of pathogens are known to challenge HSCs at the population level, being forced to respond to inflammation-mediated organismal demand to replenish the myeloid cell pool. However, less is known about the degree of heterogeneity in the HSCs' response to inflammation at the single cell level. Here, using a natural murine malaria model and an NHS-ester biotin dilution assay we identify two subsets of HSCs, BiotinLo and BiotinHi, with distinct proliferation kinetics. Using combined functional, single-cell transcriptomics and phenotypic analyses, we uncover that BiotinHi HSCs remain highly functional despite expressing strong interferon response signatures. These resilient HSCs are more poised to enter cell cycle than control HSCs, but do not divide. They maintain less active mitochondria and express higher levels of CD74 and MHC-II. Additionally, they express higher levels of integrin β2/CD18, which suggest they may have specific interactions with the bone marrow microenvironment. Similar patterns of NHS-ester biotin dilution were elicited by LPS and poly (I:C) challenges. These findings highlight previously unmeasured heterogeneity in the response of HSCs to acute infection-induced inflammation and demonstrate that a likely reserve pool of HSCs remains highly functional during Plasmodium infection not because cells are shielded, but because they maintain a stemness associated metabolic profile despite effectively sensing inflammation.

DOI: https://doi.org/10.1182/blood.2025032368
Transplant Cell Ther. 2026 Sep 11. pii: S2666-6367(26)00724-4. [Epub ahead of print]

Mutational Landscape and Clonal Dynamics in AML Undergoing PTCy Hematopoietic Cell Transplantation.

Marta Villalba, José V Gil, Juan Montoro, Aitana Balaguer-Roselló, Pedro Asensi Cantó, Pablo Granados, Inés Gómez, Pilar Solves, Brais Lamas, Ana Bataller Alfonso, Alberto Louro, Javier de la Rubia, Miguel Á Sanz, Eva Barrragán, Jaime Sanz.

  To improve risk stratification, we performed targeted NGS at diagnosis in 191 patients with AML undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. We also investigated clonal evolution using paired diagnostic and relapse samples from 39 individuals. A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. Incorporating TP53 and WT1 into risk models, recognizing context-dependent effects of DNMT3A and RUNX1, and applying longitudinal genomic monitoring may help guide personalized strategies to prevent relapse. Extended abstract BACKGROUND Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), yet the genetic mechanisms underlying post-transplant relapse remain poorly understood, particularly in the era of post-transplant cyclophosphamide (PTCy). Characterizing the mutational landscape at diagnosis and the clonal evolution leading to relapse may improve post-transplant risk stratification and identify opportunities for personalized surveillance and intervention. OBJECTIVES To characterize the diagnostic mutational landscape, evaluate its prognostic significance, and investigate clonal evolution from diagnosis to relapse in AML patients undergoing myeloablative HCT with PTCy-based graft-versus-host disease prophylaxis. STUDY DESIGN We performed targeted next-generation sequencing (NGS) at diagnosis in 191 consecutive AML patients undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. Paired diagnostic and relapse samples were available for 39 patients to evaluate clonal evolution. RESULTS A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in ∼70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. CONCLUSIONS This study provides a comprehensive characterization of the mutational landscape and clonal evolution of AML undergoing contemporary PTCy-based allogeneic HCT. TP53 and WT1 identify patients at particularly high risk of post-transplant relapse, whereas NPM1 retains favorable prognostic significance. The frequent acquisition of new genetic lesions at relapse underscores the dynamic nature of post-transplant clonal evolution and supports longitudinal molecular monitoring together with genomically informed post-transplant surveillance and relapse-prevention strategies.

Keywords:  Clonal Dynamics; Mutational Landscape; acute myeloid leukemia; allogeneic hematopoietic cell transplantation; next generation sequencing; post-transplant cyclophosphamide

DOI:  https://doi.org/10.1016/j.jtct.2026.09.022
Blood Sci. 2026 Sep;8(3): e00296

LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.

Mutian Cao, Lizhen Cong, Yifei He, Mingyue Hao, Yuanyi Ling, Wanting Li, Mingyue Zhang, Weiping Yuan, Yajing Chu.

  Acute myeloid leukemia (AML) is a group of genetically and clinically heterogeneous malignancies characterized by clonal expansion of immature myeloid progenitors and profound disruption of normal hematopoiesis. Emerging evidence suggests that alterations in cellular homeostasis shape cancer progression. However, the mechanisms underlying AML progression remain largely unclear. Here, we identify lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme of the Lands' cycle, as a critical regulator of AML progression. Analysis of public transcriptomic datasets and patient-derived CD34+ cells revealed robust LPCAT3 overexpression in AML and an association between high LPCAT3 levels and inferior overall AML patient survival. Suppression of LPCAT3 by shRNA or CRISPR-Cas9 in MOLM-13 and THP-1 cells markedly impaired proliferation, induced apoptosis, and caused G0/G1 cell-cycle arrest. Conversely, enforced overexpression promoted cell survival. In xenograft murine models, LPCAT3 depletion reduced leukemic burden. RNA-seq following LPCAT3 loss showed that genes differentially expressed were significantly enriched in granulocyte chemotaxis-related pathways, suggesting a role of LPCAT3 in modulation of leukemic differentiation programs and microenvironmental interactions. Collectively, these data established that LPCAT3 as a previously unrecognized mediator of AML cell fitness and as a potential therapeutic target.

Keywords:  Acute myeloid leukemia; Apoptosis; Cell proliferation; Chemotaxis; Immune microenvironment; LPCAT3

DOI:  https://doi.org/10.1097/BS9.0000000000000296
Br J Haematol. 2026 Sep 08.

Estimated pulse wave velocity as a marker of major adverse cardiovascular events in essential thrombocythaemia and polycythaemia vera.

Alessandro Costa, Olga Mulas, Federica Pilo, Eleonora Atzeni, Martina Pettinau, Daniela Mantovani, Giovanni Caocci.

  Estimated pulse wave velocity (ePWV), a simple surrogate of arterial stiffness, predicts cardiovascular events in general and oncology populations, but its relevance in myeloproliferative neoplasms (MPN) is unknown. We evaluated the association of baseline ePWV with major adverse cardiovascular events (MACE) and overall survival (OS) in 664 patients with essential thrombocythaemia (n = 477) or polycythaemia vera (n = 187). Median ePWV was 11.1 m/s (interquartile range [IQR], 9.2-12.9), and 72.1% met criteria for early vascular ageing (≥9.4 m/s). Over a median follow-up of 67.4 months, 58 first MACE (8.7%) and 58 deaths (8.7%) occurred. In multivariable cause-specific Cox models, each 1 m/s higher baseline ePWV was independently associated with MACE (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.02-1.32; p = 0.025). The adjusted HRs were 1.18 (95% CI 1.00-1.39; p = 0.054) for arterial thrombosis and 0.98 (95% CI 0.74-1.28; p = 0.860) for venous thromboembolism. For OS, ePWV lost significance after adjustment for age (HR 0.92, p = 0.670). Among JAK2-mutated patients, JAK2 V617F variant allele fraction showed a significant correlation with ePWV (ρ = 0.134; p = 0.022). These findings identify ePWV as a scalable marker of vascular ageing associated with cardiovascular risk in MPN, warranting prospective validation.

Keywords:  estimated pulse wave velocity; major adverse cardiovascular events; myeloproliferative neoplasms; survival; thrombosis

DOI:  https://doi.org/10.1111/bjh.70820
Nat Rev Cancer. 2026 Sep 08.

A single-cell lens into the co-evolution of genotypes and phenotypes in cancer.

Franco Izzo, Tamara Prieto, Catherine Potenski, Dan A Landau.

Genetic heterogeneity and clonal outgrowths are observed even in otherwise healthy human tissues, shaping the genetic composition of cell populations in non-malignant disease and during physiological ageing. This clonal mosaicism likely provides the pre-cancerous seeds for malignant transformation. Once a tumour arises, clonal evolution poses a major challenge to achieving cure, as clonal diversification provides an expanded number of substrates upon which therapy can act as a selective pressure, leading to the selection of resistant clones that ultimately fuel disease recurrence. Understanding somatic clonal evolution requires not only mapping genetic diversity but also defining the resulting phenotypes that provide a fitness advantage to mutated clones. This Review discusses multimodal single-cell technologies that enable the measurement of genotypes and additional molecular features from the same cell. These technologies unveil mutant-specific phenotypic traits, often show cell-state specificity in genotype-phenotype effects and can define therapeutic vulnerabilities for precision elimination of disease-propagating mutant cells. Furthermore, the combination of phylogenetic reconstruction with phenotypic measurements allows for the temporal mapping of clonal evolution and phenotypic plasticity. These breakthroughs have created a unique opportunity to define, directly in primary human samples, the mechanisms underlying clonal expansion in both healthy and malignant tissues.

DOI: https://doi.org/10.1038/s41568-026-00970-8
Science. 2026 Sep 10. 393(6816): eady0339

Extensive and differential platinum chemotherapy mutagenesis in livers of children.

Anna Wenger, Jean-Baptiste Vannier, Henry Lee-Six, Robin Loesch, Giulia Emanuelli, Manas Dave, Mehdi Layeghifard, Andrew R J Lawson, Federico Abascal, Pantelis A Nicola, Taryn D Treger, Toochi Ogbonnah, Conor Parks, Thomas R W Oliver, Jonathan Kennedy, Angus Hodder, Nathaniel D Anderson, Felipe Luz Torres Silva, Mi K Trinh, Thomas Dowe, Marwo Habarwaa, James J Sun, Sergio Assia-Zamora, Miriam Cortes-Cerisuelo, Wayel Jassem, Charlotte Town, Anil Dhawan, Vandana Jain, Karin Straathof, Maesha Deheragoda, Iñigo Martincorena, Liina Palm, J Ciaran Hutchinson, Tim H H Coorens, Claire Trayers, Mariia Yuneva, Nigel Heaton, Adam Shlien, Yoh Zen, Foad J Rouhani, Sam Behjati.

Childhood cancer survivors often experience late adverse effects that may be linked to chemotherapy mutagenesis. We studied chemotherapy mutagenesis in normal pediatric tissues using duplex sequencing (NanoSeq) to enable the detection of mutations from single DNA molecules. We found that platinum chemotherapeutics increased the mutation burdens of normal pediatric tissues to levels seen in adults. In the liver, platinum agents imparted a tissue-specific mutational signature that was absent from other tissues. Gene-focused duplex sequencing revealed that chemotherapy mutagenesis generates a great diversity of nonsynonymous variants, some of which may have functional potential, such as leukemogenic variants in blood. Our findings demonstrate extensive chemotherapy mutagenesis in normal tissues of children, which may provide a plausible link between chemotherapy exposure and adverse effects in later life.

DOI: https://doi.org/10.1126/science.ady0339
Circulation. 2026 Sep 08.

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

Mustafa Yalcinkaya, Cheng-Chieh Hsu, Linke Li, Ranran Wang, David Ngai, Pablo Sánchez Vela, Ines Fernandez-Maestre, Malgorzata Olszewska, Wenli Liu, Miao Chen, Sandra Schiavone, Tong Xiao, Eirini P Papapetrou, Nan Wang, Ross Levine, Zhi Yu, Ira Tabas, Alan R Tall.

   BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied.
METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet.
RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank.
CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

Keywords:  LDL lowering; Trem2hi macrophages; actin polymerization; atherosclerosis; clonal hematopoiesis; efferocytosis; glycolysis

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080527
Expert Rev Hematol. 2026 Sep 12. 1-12

Managing thrombotic risk in myeloproliferative disorders.

Gerard Gurumurthy, Minji Ho, Jecko Thachil, Priya Sriskandarajah.

   INTRODUCTION: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders associated with arterial and venous thrombosis. Thrombotic risk reflects conventional vascular factors and disease-specific thromboinflammatory biology. Thrombosis remains a major cause of morbidity and mortality in MPNs despite contemporary guidelines. Thus, there remains a challenging therapeutic uncertainty across diverse clinical presentations.
AREAS COVERED: We reviewed PubMed-listed articles on the epidemiology, mechanisms, risk stratification and clinical management of thrombosis in classical Philadelphia-negative MPNs. We discuss evidence for aspirin, hematocrit control, cytoreduction and anticoagulation choice. We also examine management in special populations such as in pregnancy and frailty. Lastly, we give an overview on the emerging use of Direct oral anticoagulants (DOACs) in unusual site thrombosis in this setting.
EXPERT OPINION: Thrombosis in MPNs should not be treated as a single entity. Arterial, venous and unusual-site events all differ in biology and this can have therapeutic implications. Future progress requires personalized strategies that balance thrombosis prevention, bleeding risk and clonal disease control in a heterogenous group.

Keywords:  Bleeding; Direct oral anticoagulants; Myeloproliferative neoplasms; thromboinflammation; thrombosis

DOI:  https://doi.org/10.1080/17474086.2026.2732981
Cell Rep. 2026 Sep 08. pii: S2211-1247(26)00967-8. [Epub ahead of print]45(9): 117889

Berberine, a natural molecular glue degrader, overcomes CML resistance via TRIM28-mediated HIF1α ubiquitination and subsequent ferroptosis.

Rui Su, Rongjun Xu, Wenjing Shi, Wenjing Song, Xingri Zhan, Yiling Long, Xiuyuan Wang, Hong Nie, Jia Fei.

  BCR-ABL1-independent resistance remains a major challenge in chronic myeloid leukemia (CML). These resistant cells exhibit elevated basal reactive oxygen species (ROS), which creates a therapeutic vulnerability. We show that berberine (BBR) acts as a natural molecular glue degrader of Hypoxia-Inducible Factor 1 Alpha (HIF1α) to exploit this vulnerability. BBR directly binds HIF1α at E816, stabilizing its interaction with the E3 ubiquitin ligase TRIM28, which subsequently promotes K48-linked ubiquitination of HIF1α. HIF1α degradation transcriptionally suppresses PDE4D, leading to cyclic AMP (cAMP) accumulation and activation of the xCT axis, depleting glutathione. BBR also induces metallothionein-mediated metal ion dyshomeostasis by upregulating MT1X, MT2A, and SLC30A8 mRNA levels, sequestering Cu2+/Zn2+ and inhibiting SOD1. These effects synergistically upregulate ROS to trigger ferroptosis, overcoming BCR-ABL1-independent resistance in vivo and in vitro. Thus, our findings identify an oxidative stress vulnerability in BCR-ABL1-independent resistant cells and show that BBR, a natural molecular glue degrader, exploits this vulnerability through HIF1α ubiquitination and degradation. This leads to elevated ROS that subsequently triggers ferroptosis, thereby offering a new therapeutic strategy against BCR-ABL1-independent resistance.

Keywords:  BCR-ABL1-independent resistance; CP: cancer; CP: molecular biology; HIF1α; berberine; ferroptosis; natural molecular glue degrader; ubiquitin-mediated degradation

DOI:  https://doi.org/10.1016/j.celrep.2026.117889