bims-tremyl 2025-11-16 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–11–16
sixteen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
CPX-351 versus daunorubicin, cytarabine plus gemtuzumab ozogamicin in older adults with non-adverse risk AML: NCRI AML18.
BRD9 depletion-mediated ALOX5 upregulation via chromatin dysregulation induces ferroptosis in SF3B1-mutant hematopoiesis.
Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.
Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.
The splicing factor PTBP1 interacts with RUNX1 and is required for leukemia cell survival.
Novel and emerging therapeutic strategies for clonal haematopoiesis.
Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.
Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.
Venetoclax plus hypomethylating agents as effective bridge therapy to allogeneic stem cell transplant in relapsed/refractory acute myeloid leukaemia: A subanalysis of the AVALON study.
Mutant NPM1 modulates PDCD4 ubiquitination degradation and facilitates leukemogenesis.
CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy.
A scoring system to predict life-threatening thromboischemic events in patients with acute promyelocytic leukemia: the PETHEMA/PALG study.
Second malignancies among older patients with classical myeloproliferative neoplasms treated with ruxolitinib.
Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
A non-canonical lymphoblast in refractory childhood T-cell leukaemia.

Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]

Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.

Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.

Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.

DOI: https://doi.org/10.1182/blood.2025028933
Blood. 2025 Nov 14. pii: blood.2025031006. [Epub ahead of print]

CPX-351 versus daunorubicin, cytarabine plus gemtuzumab ozogamicin in older adults with non-adverse risk AML: NCRI AML18.

Steven Knapper, Laura W Dillon, Malavika Babu, Abin Thomas, Ian Thomas, Christopher S Hourigan, Georgia M Andrew, Richard James Dillon, Amanda Frances Gilkes, Nuria Marquez-Almuina, Sophie King, Nicholas McCarthy, Reem Bahr, Rasha W Al-Ali, Louisa Stone, Tom Coats, Jennifer L Byrne, Simone Green, Ulrik Malthe Overgaard, Rob S Sellar, Mike Dennis, Priyanka Mehta, Robert K Hills, Sylvie D Freeman, Nigel H Russell.

We compared daunorubicin/AraC plus fractionated gemtuzumab (DAGO2) with CPX-351 (CPX) (1:2 randomisation) in 439 patients ≥60yrs (median age 68yrs) without known adverse-risk cytogenetics entering the NCRI AML18 version2 trial (NCT02272478). Median follow-up was 35 months. Patients not in MRD-negative remission after course-1 could enter a second randomization between standard versus intensified chemotherapy. Post course-1 response rates were greater after DAGO2 (CR+CRi, 60% vs 47.5%, OR 0.61 95%CI 0.41-0.91, p=0.016). Following course-2 the overall response was not significantly different, 85% for DAGO2 vs 78% for CPX (OR 0.64, 95%CI 0.39-1.09, P=0.095). More patients attained CR with MRD negativity post course-1 in the DAGO2 arm (47% vs 29% for CPX, OR 0.46 95%CI 0.29-0.72, p=0.004). We observed better 3yr EFS (34% vs 27%, HR 0.73 95%CI 0.57-0.93, P=0.012) and OS (52% vs 35%, HR 0.62, 95%CI 0.46-0.83, P=0.001) with DAGO2. In a stratified analysis, CPX did not provide a survival benefit in patients with MDS-related mutations (HR 1.40, 95%CI 0.97-2.03) and was associated with poorer survival in patients with NPM1 (HR 2.83 95%CI 1.17-6.82) and FLT3 mutations (HR 2.14, 95%CI 0.98-4.68). 37% of patients were transplanted in CR1 and this did not differ by randomization. Survival post-transplant did not differ between arms. For patients entering the course-2 randomisation (n=107) survival was equivalent between standard versus intensified CPX doses (P=0.565).In this population of older patients without known adverse-risk cytogenetics, DAGO2 resulted in superior survival compared to CPX. CPX did not benefit those with MDS-related mutations over DAGO2.

DOI: https://doi.org/10.1182/blood.2025031006
Int J Hematol. 2025 Nov 11.

BRD9 depletion-mediated ALOX5 upregulation via chromatin dysregulation induces ferroptosis in SF3B1-mutant hematopoiesis.

Wataru Saika, Hiromi Yamazaki, Shota Tanaka, Min Lin, Seigi Oshima, Ziyu Gao, Masaki Nomura, Weijia Zang, Yui Koike, Muran Xiao, Hiromi Ito, Naomi Matsumoto, Takaya Yamasaki, Koutarou Nishimura, Makoto Murata, Daichi Inoue.

  SF3B1 mutations are among the most common splicing factor mutations in myeloid malignancies, yet the mechanisms linking aberrant splicing to metabolic phenotypes remain incompletely understood. We previously demonstrated that SF3B1 mutations cause nonsense-mediated decay of BRD9, a core component of the non-canonical BAF chromatin remodeling complex. Here, we investigated how the SF3B1-BRD9 pathway contributes to metabolic reprogramming in hematopoietic cells. Using BRD9-depleted murine models and analyses of SF3B1-mutated samples, we found that BRD9 depletion markedly upregulates ALOX5, which plays a key role in lipid peroxidation, particularly by oxidizing polyunsaturated fatty acids. BRD9 and ALOX5 expressions are negatively correlated, and the presence of SF3B1 mutations is associated with ALOX5 upregulation in AML datasets. Notably, transcriptomic analysis demonstrated preferential upregulation of ALOX5 in mature myeloid lineages rather than stem/progenitor fractions. Mechanistically, integrated RNA-seq/ChIP-seq and Hi-C analyses revealed that BRD9 loss enhances CTCF occupancy at the ALOX5 locus boundary, enabling aberrant chromatin loop formation that drives transcriptional activation. These events increase lipid peroxidation and ferroptosis susceptibility in hematopoietic cells as evidenced by enhanced BODIPY-C11 oxidation and erastin sensitivity. Our findings reveal a spliceosome-to-chromatin-to-metabolism pathway in which SF3B1 mutations promote ferroptosis through BRD9-mediated chromatin dysregulation, highlighting the previously unrecognized metabolic rewiring in myeloid malignancies.

Keywords:   SF3B1 mutations; ALOX5; BRD9; Lipid peroxidation; Myelodysplastic syndrome

DOI:  https://doi.org/10.1007/s12185-025-04105-x
Nat Genet. 2025 Nov 11.

Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.

Tetsuichi Yoshizato, Christer Nilsson, Francesca Grasso, Kari Högstrand, Stefania Mazzi, Axel Winroth, Madeleine Lehander, Indira Barbosa, Gunilla Waldin, Teresa Mortera-Blanco, Monika Jansson, Mikaela Hillberg Widfeldt, Affaf Aliouat, Margs S Brennan, Ellen Markljung, Amy Hillen, Edwin Chari, Eva Hellström-Lindberg, Warren W Kretzschmar, Petter S Woll, Sten Eirik W Jacobsen.

Dynamic steady-state lineage contribution of human hematopoietic stem cell (HSC) clones needs to be assessed over time. However, clonal contribution of HSCs has only been investigated at single time points and without assessing the critical erythroid and platelet lineages. Here we screened for somatic mutations in healthy aged individuals, identifying expanded HSC clones accessible for lineage tracing of all major blood cell lineages. In addition to HSC clones with balanced contribution to all lineages, we identified clones with all myeloid lineages but no or few B and T lymphocytes or all myeloid lineages and B cells but no T cells. No other lineage restriction patterns were reproducibly observed. Retrospective phylogenetic inferences uncovered a 'hierarchical' pattern of descendant subclones more lineage biased than their ancestral clone and a more common 'stable' pattern with descendant subclones showing highly concordant lineage contributions with their ancestral clone, despite decades of separation. Prospective lineage tracing confirmed remarkable stability over years of HSC clones with distinct lineage replenishment patterns.

DOI: https://doi.org/10.1038/s41588-025-02405-w
J Hematol Oncol. 2025 Nov 14. 18(1): 102

Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.

Jorge Cortes, Antonio Curti, Pierre Fenaux, Brian A Jonas, Jürgen Krauter, Pau Montesinos, Christian Récher, David C Taussig, Eunice S Wang, Justin Watts, Andrew Wei, Karen Wl Yee, Hua Tian, Aaron Sheppard, Christophe Marzac, Stephane de Botton.

   BACKGROUND: Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.
METHODS: Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).
RESULTS: At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (P < 0.001; 95% CI, 27-43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9-5.6 months). Among responders, 33% achieved CR/CRh within 2-4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (n = 71; 95% CI, 40-56.7). Median duration of CR/CRh was 25.3 months (95% CI, 13.5-not reached), and median overall survival (OS) was 11.5 months (95% CI, 8.3-15.5). Patients with 1-2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.
CONCLUSION: These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.
TRIAL REGISTRATION: NCT02719574.

Keywords:  Mutant IDH1 inhibitor; Olutasidenib; Relapsed/refractory AML; Targeted therapy

DOI:  https://doi.org/10.1186/s13045-025-01751-w
Leukemia. 2025 Nov 10.

The splicing factor PTBP1 interacts with RUNX1 and is required for leukemia cell survival.

Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K Dobish, Sipra Panda, Shannon M Buckley, Samantha A Swenson, Sandipan Brahma, M Jordan Rowley, R Katherine Hyde.

Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 in regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.

DOI: https://doi.org/10.1038/s41375-025-02799-w
Haematologica. 2025 Nov 13.

Novel and emerging therapeutic strategies for clonal haematopoiesis.

Mohsen Hosseini, Steven M Chan.

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

DOI: https://doi.org/10.3324/haematol.2025.287443
Br J Haematol. 2025 Nov 12.

Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.

Benjamin J Lee, Shawn P Griffin, Jean Doh, Anthony Quach, Yujiao Sun, Piyatida Chumnumsiriwath, Stefan O Ciurea, Jorge Ramos-Perez, Polina Bellman, Deepa Jeyakumar, Piyanuch Kongtim, Kiran Naqvi.

  Induction chemotherapy in fit de novo acute myeloid leukaemia (AML) patients has historically combined an anthracycline with standard-dose cytarabine ('7 + 3') despite complete response (CR) rates of 50%-70%. In May 2023, our institution adopted the utilization of cladribine, cytarabine, idarubicin and venetoclax (CLIA-VEN) for intensive remission-induction therapy. In this retrospective study, outcomes of newly diagnosed adult AML patients who were consecutively treated with CLIA-VEN (n = 20; 2023-2025) were compared to a historical cohort that received 7 + 3 (n = 42; 2016-2023). The median interquartile range [IQR] age was 54 [42-63] years, 54% were male and 58% had European LeukemiaNet (ELN) 2022 adverse-risk disease. CLIA-VEN was associated with a higher cumulative incidence of composite CR (CCR) (90% vs. 54.8%; p = 0.002) and minimal residual disease (MRD)-negative CCR (93.8% vs. 40.9%; p < 0.001) at 28 days. Any grade ≥ 2 end-organ toxicity (45% vs. 59.5%; p = 0.28) and early mortality (0% vs. 16.7%; p = 0.09) were not increased with CLIA-VEN. Utilizing propensity score guided inverse probability treatment weighting to balance baseline demographics, receipt of CLIA-VEN was associated with improved overall survival (p = 0.002). Acknowledging the limitations of a retrospective single-centre study, our data suggest that CLIA-VEN has higher efficacy without increasing toxicity and the potential to prolong survival compared to the current standard of care in de novo AML patients.

Keywords:  CLIA; MRD; acute myeloid leukaemia; venetoclax; ‘7 + 3’

DOI:  https://doi.org/10.1111/bjh.70253
Cancer Res. 2025 Nov 11.

Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.

Vincent Rondeau, Suraj Bansal, Marco M Buttigieg, Andy G X Zeng, Darryl Y Chan, Michelle Chan-Seng-Yue, Liqing Jin, Jessica McLeod, Meghan Kates, Elisa Donato, Patrick Stelmach, Caitlyn Vlasschaert, Yitong Yang, Aarushi Gupta, Sofia Genta, Enrique Sanz-Garcia, Liran Shlush, Mauricio Ribeiro, Marcus O Butler, Sagi Abelson, Mark D Minden, Samuel D Saibil, Steven M Chan, Michael J Rauh, Andreas Trumpp, John E Dick, Robert J Vanner.

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen receptor T cell function, suggesting it might also impact immunotherapy response. Here, we found that hematopoietic Tet2 mutation in mouse models enhanced the immune checkpoint blockade (ICB) response, which required the combined presence of phagocytes, CD4+, and CD8+ T cells. The effect was lost with myeloid- or T-cell restricted Tet2 inactivation or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. Clinically, tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, this work demonstrates that hematopoietic TET2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3329
Br J Haematol. 2025 Nov 12.

Venetoclax plus hypomethylating agents as effective bridge therapy to allogeneic stem cell transplant in relapsed/refractory acute myeloid leukaemia: A subanalysis of the AVALON study.

Elisabetta Petracci, Francesca Pavesi, Luca Castagna, Patrizia Zappasodi, Cristina Papayannidis, Calogero Vetro, Vincenzo Federico, Alessandro Cignetti, Erika Borlenghi, Nicola Fracchiolla, Luca Facchini, Luca Maurillo, Ernesta Audisio, Massimo Bernardi, Felicetto Ferrara, Francesco Lanza, Carmine Selleri, Ilenia Manfra, Claudio Cerchione, Jacopo Nanni, Andrea Davide Romagnoli, Giovanni Marconi, Chiara Zingaretti, Ivana Lotesoriere, Federica Gigli, Giovanni Martinelli, Elisabetta Todisco.



Keywords:  acute myeloid leukaemia; allogeneic haematopoietic stem cell transplantation; relapsed/refractory AML

DOI:  https://doi.org/10.1111/bjh.70248
iScience. 2025 Nov 21. 28(11): 113776

Mutant NPM1 modulates PDCD4 ubiquitination degradation and facilitates leukemogenesis.

Chuangxuan Liang, Jing Ke, Zhenyu Zhang, Huarong Guo, Hongxin Shang, Danwen Liu, Shan Li, Fuyun Wu.

  PDCD4 is a nuclear-cytoplasmic shuttling protein. It functions as a protein translation inhibitor and regulates cancer development. Here, we show that PDCD4 interacts with NPM1. NPM1 mutation results in cytoplasmic localization of mutated protein, NPMc+, which plays critical roles in leukemogenesis. We demonstrate that NPMc+ induces abnormal localization of PDCD4 in the cytoplasm and accelerates its ubiquitination degradation. Additionally, we uncover the function of PDCD4 in regulating histone deacetylation and gene transcription in the nucleus. These results imply that NPMc+ may initiate leukemia at both the transcriptional and translational levels by modulating the mislocalization and degradation of PDCD4. Finally, we show that the use of PDCD4-derived peptides to block the interaction between NPMc+ and PDCD4 exhibits a promising therapeutic effect in NPM1-mutated acute myeloid leukemia (AML) mice. Our findings suggest that the NPMc+/PDCD4 complex could be a potential therapeutic target for this subtype of AML.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.113776
Mol Ther. 2025 Nov 10. pii: S1525-0016(25)00950-5. [Epub ahead of print]

CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy.

Bernhard Lehnertz, Maéva Langouët, Sophie Corneau, Tara MacRae, Maju Joe, Edward N Schmidt, Jean-Francois Spinella, Nadine Mayotte, Susan Moore, Maria Florencia Tellechea, Isabel Boivin, Loïc Papineau, Shanti Rojas-Sutterlin, Margaux Tual, Camille Jimenez Cortes, Jalila Chagraoui, Elisa Tomellini, Virginie Desse, Etienne Gagnon, Matthew S Macauley, Guy Sauvageau.

Immunotherapies in acute myeloid leukemia (AML) are limited by shared antigen expression between leukemic and healthy hematopoietic cells, resulting in on-target toxicity. To overcome this, we developed a clinically scalable approach to engineer cord blood (CB) hematopoietic stem and progenitor cell (HSPC) grafts resistant to an established CD33-directed therapy. Combining UM171-mediated expansion with adenine base editing (ABE), we precisely disrupted the P67 epitope of CD33, centered on phenylalanine 21, which is essential for gemtuzumab ozogamicin (GO) binding. Edited variants retained CD33 expression and sialic-acid-dependent ligand binding, distinguishing this strategy from complete gene ablation. In UM171 cultures, P67 editing was efficient across multiple donors, enriched in primitive subsets, and minimally impacted expansion. In xenografts, edited grafts preserved multilineage engraftment, T-cell output, and myeloid persistence. Upon GO challenge, edited graft-derived myeloid cells were protected while CD33+ AML cells were eliminated, confirming on-tumor activity with reduced myelotoxicity. Ultra-deep exome sequencing and GUIDE-seq revealed minimal off-target activity. Together, these findings establish CD33 P67 epitope-directed base editing as a precise, scalable strategy to generate immunotherapy-compatible, UM171-expanded CB grafts that safely enable GO integration into post-transplant care.

DOI: https://doi.org/10.1016/j.ymthe.2025.11.010
Haematologica. 2025 Nov 13.

A scoring system to predict life-threatening thromboischemic events in patients with acute promyelocytic leukemia: the PETHEMA/PALG study.

Rebeca Rodríguez-Veiga, Cristina Gil, Marta Sobas, Laura Torres-Miñana, Carmen Botella, Javier De la Serna, Teresa Bernal, Olga Salamero, Cristina Otero, Irene Navarro-Vicente, Carlos De Miguel, Ana Garrido, Susana Vives, Juan Bergua, Manuel Pérez-Encinas, Lorenzo Algarra, José González-Campos, Maria Del Mar Caballero Gómez, Maria Virginia Prates, Celina Benavente, Mar Tormo, Marta Cervera, Patricia Fazio, Maria Elena Amutio, Raimundo García, Helena Pomares, Belén Vidriales, Josefina Serrano, Mª Luz Amigo, Vicente Rubio, Ágata Almela, Manuel Barrios, Claudia Lucia Sossa-Melo, Monika Paluszewska, Andrés Novo, Tomasz Gromek, Gabriela Rodríguez-Macías, Jolanta Oleksiuk, Pilar Lloret-Madrid, Pau Montesinos.

Acute promyelocytic leukemia (APL) is a highly curable leukemia characterized by life-threatening coagulopathy leading to hemorrhagic and thrombo-ischemic events. We analyzed the incidence, outcomes and risk-factors of thromboischemic events in a large series of 1210 patients with newly diagnosed APL reported to the PETHEMA registry. Therapy consisted on ATRA and chemotherapy (AIDA-based). Median age of patients was 46 years (range 2-90 years). Fifty-eight patients (5%) did not start AIDA regimen as they were unfit for chemotherapy, or they died early before initiating ATRA. A total of 195 (16%) patients developed thrombo-ischemic events, the most frequent being superficial-vein and/or central catheter-related (6.9%) followed by central nervous system (2.2%), deep-vein thrombosis (2.1%), pulmonary embolism (2.1%), acute myocardial infarction (1.6%), or other locations (1.2%). Thromboischemic events mostly occurred at diagnosis and during induction (4.0%, and 9.3%, respectively). Patients developing life-threatening thrombo-ischemic events (i.e, excluding superficial and/or catheter-related) at diagnosis/induction had 31% early death rate. Prolonged aPTT, age >40 years, ECOG more than 1, platelets > 25 x 109/L, and absence of bleeding at presentation were independent risk factors for life-threatening thrombo-ischemic events. Using these variables (1 point each) we developed and validated the Thromb-On risk score, identifying a high-risk group (3 to 5 points). The Thromb-On risk score was validated in a cohort of 585 patients treated since 2017 with arsenic trioxide plus ATRA (.

DOI: https://doi.org/10.3324/haematol.2025.288112
Blood Neoplasia. 2025 Nov;2(4): 100159

Second malignancies among older patients with classical myeloproliferative neoplasms treated with ruxolitinib.

Rong Wang, Jessica M Stempel, Rory M Shallis, Scott F Huntington, Amer M Zeidan, Natalia Neparidze, Mengyang Di, Jan Philipp Bewersdorf, Lourdes Mendez, Xiaomei Ma, Nikolai A Podoltsev.

Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) associated with an increased risk of development of second primary malignancies (SMs). The reasons for solid and lymphoid SMs are unclear, but a therapy-related effect has been invoked. Although an increased risk of nonmelanoma skin cancers is associated with the use of ruxolitinib (RUX), its influence on the development of other forms of SMs remains controversial. We conducted a retrospective cohort analysis to assess associations between RUX and SMs among older patients diagnosed with MPN from 2012 to 2019 in the Surveillance, Epidemiology, and End Results-Medicare-linked database. We identified 6043 patients (2396 with PV, 2944 with ET, 703 with MF) with a median age of 76 years (interquartile range [IQR], 71-82). After a median follow-up of 3.66 (IQR, 2.25-5.17) and 3.02 years (IQR, 1.84-4.75) for 513 RUX users and 5530 nonusers, respectively, 469 patients developed an SM: 383 solid and 86 lymphoid. In the multivariable proportional subdistribution hazard regression model with death as a competing risk, the risk of developing any SM did not differ by RUX use status (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.65-1.42; P = .84) or by proportion of days covered by RUX (every 10% increase; HR, 1.00; 95% CI, 0.96-1.05; P = .95). RUX exposure did not affect the risk of solid SM (HR, 0.77; 95% CI, 0.48-1.23; P = .27) or lymphoid SM (HR, 1.73; 95% CI, 0.79-3.80; P = .17). Our results suggest that RUX use does not increase the risk of SM in older patients with MPN.

DOI: https://doi.org/10.1016/j.bneo.2025.100159
Nat Metab. 2025 Nov 13.

Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.

Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.

Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.

DOI: https://doi.org/10.1038/s42255-025-01419-2
Nat Commun. 2025 Nov 12. 16(1): 9397

A non-canonical lymphoblast in refractory childhood T-cell leukaemia.

Bram S J Lim, Holly J Whitfield, Mi K Trinh, Gianna Bloye, Rebecca Thomas, Nathaniel D Anderson, Anna Wenger, Angus Hodder, Taryn D Treger, Henry Lee-Six, Tim H H Coorens, Conor Parks, Toochi Ogbonnah, Petri Pölönen, Charles G Mullighan, David T Teachey, Jason Xu, Kai Tan, Melanie Hagleitner, Lennart Kester, Frank N van Leeuwen, Gordon Beattie, Marc R Mansour, Owen Williams, Jack Bartram, Stuart Adams, Laura Jardine, Sam Behjati, David O'Connor.

Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility.

DOI: https://doi.org/10.1038/s41467-025-65049-8