bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–05–31
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Mutant IDH1 blocks neutropoiesis by repressing myeloid progenitor programs.
  2. A proposed refined definition of acute myeloid leukaemia patients ineligible for intensive therapy: The Integrated Comorbidity-ECOG-Age criteria.
  3. Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
  4. AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
  5. Ultra-high-sensitivity next-generation sequencing-based MRD predicts outcome in intensively treated older patients with acute myeloid leukemia: results from the ALFA-1200 cohort.
  6. L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.
  7. The fetal specific gene LIN28B is essential for human fetal B-lymphopoiesis and initiation of KMT2A::AFF1 infant leukemia.
  8. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML.
  9. Human haematopoietic stem cells remember inflammatory stress.
  10. Prognostic Score for Myelodysplastic Syndromes Based on Molecular Evolution.
  11. Restricting glycine uptake with bitopertin improves erythropoiesis in preclinical models of Diamond-Blackfan anemia.
  12. Outcomes of mixed phenotype acute leukemia undergoing allogeneic stem cell transplantation: a retrospective study of the ALWP of EBMT.
  13. LDLRAD2 drives glycolysis and angiogenesis to promote extramedullary infiltration in acute myeloid leukemia.
  14. Dysregulated HELLS expression alters cellular processes and serves as a potential prognostic marker in acute myeloid leukemia.
  15. Distinct Longitudinal Patterns of Basal and Squamous Cell Carcinoma in Polycythemia Vera and Essential Thrombocythemia.
  16. A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells.
  17. Real-world heterogeneity in the prognostic value of pre-transplant flow cytometry measurable residual disease in acute myeloid leukemia in first complete remission: CIBMTR analysis.
  18. Enhanced formaldehyde clearance ameliorates differentiation-induced genotoxicity in Fanconi anemia mutant cells.
  19. Clinical Heterogeneity and Outcome of acquired PRCA: a Multicenter European Study.
  20. Chronic myeloid leukemia: incorporation of recent advances into current treatment algorithms.
  21. Characteristics and Prognostic Implications in Newly Diagnosed KMT2Ar AML: A Multicenter Study of the ECLA Group.
  22. Further insights into the application of the TFR prognostic score (TPS) in CML patients attempting TFR.
  23. Outcomes of patients with de novo and secondary acute myeloid leukaemia treated with front-line hypomethylating agents and venetoclax: A retrospective Italian study.
  24. Next generation sequencing-based measurable residual disease detection predicts outcomes in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.
  25. Lorlatinib-induced remission in refractory acute myeloid leukemia with an anaplastic lymphoma kinase fusion.
  26. Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
  1. Blood. 2026 May 26. pii: blood.2025031268. [Epub ahead of print]
    Mutant IDH1 blocks neutropoiesis by repressing myeloid progenitor programs.
    Mariam Hakobyan, Jens Langstein, María José Ramos Medina, Emely Kleinert, Maximilian Schönung, Mark Hartmann, Hannah Rohdjess, Jessica Wojtarowicz, Sina Staeble, Melissa Türe, Yasmine Pobiedonoscew, Rainer Claus, Lars Bullinger, Christopher C Oakes, Katharina Zoldan, Michael Cross, Uwe Platzbecker, Niclas Kneisel, Simon Raffel, Ulrich Germing, Gregor Hoermann, Simon Haas, Karsten Rippe, Stefan Fröhling, Stefan Pusch, Christoph Plass, Michael D Milsom, Daniel B Lipka.
      IDH1 and IDH2 are frequently mutated in various cancers, including acute leukemias. However, the distinct mechanisms by which mutant IDH1 or IDH2 drive hematopoietic neoplasms remain poorly understood. Here, we analyzed DNA methylation in IDH1- and IDH2-mutant AML and found neutrophil lineage-specific epigenetic alterations in IDH1-mutant cases that went along with severely impaired neutrophil differentiation. Transcriptional analysis of normal hematopoiesis in humans and mice revealed a strong physiological upregulation of IDH1/Idh1 in myeloid progenitors. To study the functional effects of Idh1 mutations on hematopoiesis in a pre-leukemic setting, we used a genetically engineered inducible mouse model expressing a heterozygous Idh1 mutation under control of the endogenous promotor. Our study revealed a cell-intrinsic block in neutrophil differentiation caused by repression of myeloid transcription programs in neutrophil progenitors. This included impaired expression of Cebpe, which encodes a key transcription factor regulating neutrophil differentiation. Reactivation of Cebpe expression, by overexpression of its upstream regulator Cebpa or following treatment with hypomethylating agents restored differentiation, indicating that the differentiation block is reversible.In summary, we found a reversible, pre-leukemic impairment of neutrophil differentiation in IDH1-mutant hematopoiesis that correlates with elevated IDH1 expression in myeloid progenitors and likely explains the strong association of IDH1 mutations with myeloid neoplasms.
    DOI:  https://doi.org/10.1182/blood.2025031268
  2. Br J Haematol. 2026 May 30.
    A proposed refined definition of acute myeloid leukaemia patients ineligible for intensive therapy: The Integrated Comorbidity-ECOG-Age criteria.
    Daniel Weidl, Myrto Boukovala, Doris Glaser, Bettina Barthel, Lars Bullinger, Michael Heuser.
      
    Keywords:   AML ; fitness assessment; less‐intensive treatment
    DOI:  https://doi.org/10.1111/bjh.70592
  3. Clin Cancer Res. 2026 May 26.
    Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine.
    Evan C Chen, Yiwen Liu, Hayden L Bell, Jeremy Ryan, Jason Wu, Emma-Jayne Minihane, Marlise R Luskin, Eric S Winer, Rahul Vedula, Virginia Volpe, Maximillian Stahl, Daniel Roberts, Ilene Galinsky, Mary Gerard, Matthew Hersch, Jessica Lee, Donna Neuberg, Richard M Stone, Daniel J DeAngelo, Anthony Letai, Andrew A Lane, Jacqueline S Garcia.
       BACKGROUND: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective treatment for most subtypes of acute myeloid leukemia (AML), but it is less effective for other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies.
    PATIENTS AND METHODS: We conducted a Phase 1 study (NCT05455294) of dose-escalated navitoclax added to venetoclax and decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts.
    RESULTS: Sixteen subjects were enrolled. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (44%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20mg/m2 days 1-5, venetoclax 400mg/day days 1-14, and navitoclax 50mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated monocytes in subjects with monocytic disease, and higher myeloblast dependence on BCL-2 and BCL-xL in responding subjects.
    CONCLUSION: Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-4905
  4. Mol Cancer. 2026 May 27.
    AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.
    Shakti P Pattanayak, Odai Darawshi, Omid Hajihassani, Jordan M Winter, Nicole Weiler, Melanie Ott, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Daniel J Lindner, Thomas D Green, Polina Krassovskaia, Raphael T Aruleba, Kelsey H Fisher-Wellman, Jason A Mears, David Wald, Leif A Eriksson, Boaz Tirosh.
       BACKGROUND: mTORC1 activity is oncogenic. However, in the presence of chemotherapy, suppression of mTORC1 is cytoprotective. mTOR suppression requires an intact tuberous sclerosis complex (TSC), composed of TSC1, TSC2 and TBC1D7. Small molecules that activate mTOR by blocking the TSC are lacking.
    METHODS: We applied in silico docking and medicinal chemistry to generate AcTor, a potential first-of-its-kind TSC2 inhibitor. Because inhibition of TSC2 results in increased sensitivity to proteasome inhibitors, we combined AcTor and the proteasome inhibitor ixazomib (IXZ) in various cancer cell types.
    RESULTS: Potentiation of cytotoxic activity of IXZ by AcTor was observed across multiple acute myeloid leukemia (AML) cell lines and primary patient samples. The combination triggered a collapse of mitochondrial respiratory capacity, loss of mitochondrial membrane potential, accumulation of ROS and apoptosis. These attributes increased in drug-resistant AML. Transcriptomic profiling revealed that AcTor alone induced anabolic and oxidative phosphorylation programs, whereas AcTor/IXZ redirected the signaling towards stress-associated and pro-apoptotic transcriptional states, including a p53 pathway signature. In vivo studies revealed reduction in AML burden, depletion of blasts and of leukemic stem cells, and retention of activity upon relapse. AcTor/IXZ was equally potent in a TP53-mutated patient-derived xenograft model, exceeding the efficacy of standard-of-care.
    CONCLUSIONS: As a TSC2 inhibitor, AcTor should not be used alone in cancer. When combined with proteasome inhibitors, the pharmacodynamics of AcTor shifts towards the development of a mitochondrial catastrophe in AML, which is durable, broad range, agnostic to TP53 mutations and to the acquisition of resistance to common clinical anti-AML drugs.
    DOI:  https://doi.org/10.1186/s12943-026-02689-4
  5. Blood Cancer J. 2026 May 28. pii: 84. [Epub ahead of print]16(1):
    Ultra-high-sensitivity next-generation sequencing-based MRD predicts outcome in intensively treated older patients with acute myeloid leukemia: results from the ALFA-1200 cohort.
    Augustin Boudry, Laurène Fenwarth, Raphaël Itzykson, Thorsten Braun, Lionel Adès, Élise Fournier, Céline Berthon, Delphine Lebon, Stéphane De Botton, Régis Peffault de Latour, Cécile Pautas, Hervé Dombret, Emmanuel Raffoux, Claude Gardin, Karine Celli-Lebras, Claude Preudhomme, Nicolas Duployez.
      
    DOI:  https://doi.org/10.1038/s41408-026-01530-x
  6. Blood. 2026 May 26. pii: blood.2025032136. [Epub ahead of print]
    L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.
    Honglin Duan, Bohong Wang, Yawei Zheng, Yanling Lv, Ting Lu, Haoyuan Li, Pujiao Li, Ruonan Li, Xiaowei Xie, Zining Yang, Guohuan Sun, Xiangnan Zhao, Meng Yang, Yicheng He, Chang Xu, Shuangshuang Pu, Linmin Zhang, Jun Shi, ErLie Jiang, Tao Cheng, Zeping Hu, Hui Cheng.
      Understanding how metabolism governs human hematopoietic stem cells (HSCs) function is essential for advancing regenerative therapies, yet direct metabolic profiling of human HSCs has been limited by their extreme scarcity and the technical limitations of conventional methods. Here, we apply a low-input mass spectrometry-based metabolomics platform, optimized for rare cell populations, to generate metabolic profiles of 13 immunophenotypically defined hematopoietic cell types from adult human bone marrow. Using as few as ~10,000 cells per sample, we detect over 80 metabolites and uncover both conserved metabolic programs in primitive hematopoietic stem and progenitor cells (HSPCs) and lineage-specific metabolic specializations. Notably, we identify L-carnitine-driven fatty acid oxidation (FAO) as a key metabolic feature supporting HSPC function. Mechanistically, L-carnitine activates the PPARA-TFEB signalling axis, promoting mitochondrial metabolism and autophagy to preserve regenerative capacity. Functional assays in primary CD34+ HSPCs derived from healthy donors or patients with aplastic anemia confirm that L-carnitine supplementation improves stem cell function ex vivo and in vivo. Together, this work provides a foundation for human hematopoietic metabolism and reveals a targetable metabolic circuit governing HSPC regenerative fitness with therapeutic potential for improving stem cell-based interventions.
    DOI:  https://doi.org/10.1182/blood.2025032136
  7. Blood. 2026 May 29. pii: blood.2025028877. [Epub ahead of print]
    The fetal specific gene LIN28B is essential for human fetal B-lymphopoiesis and initiation of KMT2A::AFF1 infant leukemia.
    Rebecca E Ling, Alia M Welsh, Lucy Hamer, Thomas Jackson, Emily Neil, Natalina Elliott, Joe Wilson Cross, Arundhati Siddhartha Wuppalapati, Alastair L Smith, Catherine Chahrour, Okan Sevim, David A Palmer, Yavor Bozhilov, Elizabeth J Brown, Leonid Olender, Deena Iskander, Guanlin Wang, Siobhan Rice, Sorcha O'Byrne, Joe Harman, Philip Ancliff, Bethan Psaila, Adam C Wilkinson, Rhys G Morgan, Irene Ag Roberts, Thomas A Milne, Anindita Roy.
      Infant ALL (iALL) is initiated in utero, most often by rearrangement of the KMT2A gene (KMT2Ar). It carries a very poor prognosis despite a lack of additional oncogenic driver mutations common in childhood ALL. Here, we aimed to identify specific properties of human fetal hematopoietic stem/progenitor cells (HSPC) that promote leukemic transformation in KMT2Ar iALL using molecular, functional and in vivo assays. Through comparison of human fetal HSPC with adult HSPC transcriptomes we derived a fetal-specific gene signature and identified the fetal oncogene LIN28B and its downstream effectors among the top hits. These genes were also expressed in iALL. Functional assays revealed that LIN28B was essential in human fetal liver (FL) CD34+ cells to maintain proliferation and stem-like properties, and support B- and NK-lymphopoiesis. To interrogate the role of LIN28B in iALL, we utilized a human FL-derived CRISPR-Cas9 KMT2A::AFF1 model. In this CRISPRKMT2A::AFF1 model, human FL CD34+ cells fail to transform upon induction of KMT2A::AFF1 translocation in the absence of LIN28B. Furthermore, LIN28B-expressing CRISPRKMT2A::AFF1 leukemias were more proliferative in vitro and in vivo, with this advantage being lost upon LIN28B knockdown. Mechanistic studies showed that LIN28B acts by stabilizing key early B-lymphoid genes, epigenetic regulators, and cell cycle and anti-apoptotic genes. Thus, LIN28B has an essential role in normal human fetal B-lymphopoiesis, and is necessary for the initiation of KMT2A::AFF1 iALL in human fetal cells in the absence of co-operating mutations. LIN28B activity may help explain why KMT2A::AFF1 leukemias are so aggressive, making it a potential target in LIN28B-expressing leukemias.
    DOI:  https://doi.org/10.1182/blood.2025028877
  8. Blood Adv. 2026 May 27. pii: bloodadvances.2026019841. [Epub ahead of print]
    Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML.
    Nicholas J Short, Hagop M Kantarjian, Naval G Daver, Roberta S Azevedo, Omer Karrar, Courtney D DiNardo, Tapan M Kadia, Musa Yilmaz, Manuel M Maroun, Maria Catherine Rita Hachem, Gautam Borthakur, Ghayas C Issa, Elizabeth J Shpall, Uday R Popat, Xuelin Huang, Wei Qiao, Lewis Fady Nasr, Walid Macaron, Regina Abramova, Guillermo Garcia-Manero, Marina Konopleva, Farhad Ravandi.
      In patients with FLT3-mutated AML who receive frontline azacitidine plus venetoclax, relapses are commonly driven by expansion of the FLT3-mutated clone, providing rationale for "triplet" FLT3 inhibitor-based lower-intensity regimens. Here we report long-term outcomes of a phase II study of azacitidine, venetoclax and gilteritinib in adults with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. Thirty patients were treated; the median age was 71 years, and 22 (73%) had a FLT3-ITD mutation. The complete remission (CR)/CR with incomplete hematologic recovery rate was 96%, and 14 patients (47%) underwent allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. With a median follow-up of 41.5 months, 11 patients (37%) relapsed; in 67% of evaluable relapses, the FLT3 mutation was not detectable. The median RFS and OS were 23.4 and 29.7 months, respectively, and the 3-year RFS and OS rates were 43% and 46%, respectively. Among patients with FLT3-ITD-mutated AML, the median RFS and OS were 17.0 and 21.8 months, respectively, and the 3-year RFS and OS rates were 32% and 36%, respectively. The presence of a baseline RAS pathway mutation was associated with worse outcomes. Survival rates were similar regardless of HSCT in first remission. Among patients who received at least one consolidation cycle, 68% had a reduction in the dose or duration of at least one of the study drugs. The triplet regimen of azacitidine, venetoclax and gilteritinib is associated with durable remissions and encouraging long-term survival. Randomized studies comparing this regimen to standard of care approaches are warranted. This trial is registered at www.clinicaltrials.gov #NCT04140487.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019841
  9. Nature. 2026 May 27.
    Human haematopoietic stem cells remember inflammatory stress.
    Andy G X Zeng, Murtaza S Nagree, Niels Asger Jakobsen, Sayyam Shah, Angelica Varesi, Jasmine Ryu Won Kang, Alex Murison, Jin-Gyu Cheong, Sven Turkalj, Xuan Zhang, Felix A Radtke, Tsega-Ab Abera, Isabel N X Lim, Liqing Jin, Joana Araújo, Alicia G Aguilar-Navarro, Darrien Parris, Jessica McLeod, Hyerin Kim, Ho Seok Lee, Lin Zhang, Mason Boulanger, Elyssa Bader, Elias Gbeha, Christopher N Parkhurst, Elvin Wagenblast, Eugenia Flores-Figueroa, Bo Wang, Gregory W Schwartz, Leonard D Shultz, Anna S Nam, H Leighton Grimes, Steven Z Josefowicz, Philip Awadalla, Paresh Vyas, John E Dick, Stephanie Z Xie.
      Inflammation activates blood cells, contributing to ageing and malignancy1-3. Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis1-9, but how human HSCs respond and adapt to inflammatory stress is largely unknown. Here, to empirically understand this adaptation, we developed xenograft inflammation-recovery models and performed single-cell multiomics on xenografted human HSCs. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining a molecular memory of previous inflammatory treatments. The HSC-iM subset exhibited quiescence and restrained haematopoietic output. Molecularly, the HSC-iM program was enriched in HSCs from adult and paediatric samples across conditions ranging from COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. Clonal haematopoiesis mutations in HSC-iM attenuated the effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, transmission of the pro-inflammatory HSC-iM transcriptional program to differentiated immune progeny was demonstrated in xenograft and physiological settings. Finally, HSC-iM program enrichment in circulating blood cells was associated with a heightened risk score for all-cause mortality in population cohort analyses, underscoring the clinical relevance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.
    DOI:  https://doi.org/10.1038/s41586-026-10522-7
  10. NEJM Evid. 2026 Jun;5(6): EVIDoa2500124
    Prognostic Score for Myelodysplastic Syndromes Based on Molecular Evolution.
    Ivan Civettini, Federica Malighetti, Matteo Villa, Valentina Crippa, Andrea Aroldi, Fabrizio Cavalca, Alex Graudenzi, Luca Lanino, Giulia Maggioni, Torsten Haferlach, Pierre Fenaux, Uwe Platzbecker, María Díez-Campelo, Lorenza Maria Borin, Monica Fumagalli, Arianna Zappaterra, Beatrice Manghisi, Najla H Al Ali, David A Sallman, Eric Padron, Zhuoer Xie, Onyee Chan, Amer M Zeidan, Luca Mologni, Rocco Piazza, Rami S Komrokji, Matteo Giovanni Della Porta, Carlo Gambacorti-Passerini, Daniele Ramazzotti.
       BACKGROUND: Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by multistep molecular evolution and a variable risk of leukemic transformation. Given this prognostic heterogeneity, accurate risk stratification is essential for clinical decision-making. We developed ProgEvo, a proprietary framework that infers molecular evolutionary trajectories and integrates them with clinical data to improve prognostic accuracy.
    METHODS: ProgEvo was trained on 2519 patients in cBioPortal (https://www.cbioportal.org) and validated using two external cohorts: Genomed4All (2043 patients) and a Moffitt Cancer Center (MCC) cohort (2157 patients). Directional evolutionary routes were inferred and selected for prognostic modeling if they were consistently associated with leukemia-free survival. A multivariable feature selection strategy was applied to integrate evolution-consistent variables into the existing IPSS-M model.
    RESULTS: ProgEvo identified 1765 gene co-occurrences aggregated into 45 directional evolutionary routes. Of these, 18 were validated in the Genomed4All cohort. Five evolution-informed variables, two directional routes (Additional Sex Combs-Like 1 [ASXL1]→KRAS Proto-Oncogene [KRAS] and Serine and Arginine-Rich Splicing Factor 2 [SRSF2]→NRAS Proto-Oncogene [NRAS]), one co-occurrence (NRAS/RUNX Family Transcription Factor 1 [RUNX1]), and two early mutations (ATRX [ATRX Chromatin Remodeler] and Janus Kinase 2 [JAK2]) were integrated into IPSS-M to generate IPSS-M-Evo. The model with "-Evo" improved discrimination for both leukemia-free survival and overall survival, with over 40% of patients restratified in the Genomed4All data. The performance of the model was further confirmed in the MCC cohort.
    CONCLUSIONS: ProgEvo enabled inference of a molecular evolution model and integration of evolution-informed covariates into clinical prognostic frameworks, supporting the development of the IPSS-M-Evo model. A free web-based tool allows clinicians to calculate the IPSS-M-Evo score and match individual mutational profiles to cohort-derived evolutionary trajectories (https://evoclin.unimib.it/tools/evolution-graphs.html and https://evoclin.unimib.it/tools/ipssmevo.html). (Funded by the European Union and others.).
    DOI:  https://doi.org/10.1056/EVIDoa2500124
  11. Blood Red Cells Iron. 2025 Sep;pii: 100010. [Epub ahead of print]1(2):
    Restricting glycine uptake with bitopertin improves erythropoiesis in preclinical models of Diamond-Blackfan anemia.
    Raymond T Doty, Adam D Munday, Hannah Cottnair, Sarah E Funk, David J Young, Cynthia E Dunbar, Min Wu, Janis L Abkowitz.
      Diamond-Blackfan anemia (DBA) results from germ line haploinsufficiency of 1 of at least 26 distinct ribosomal proteins. Although patients with DBA have hematopoietic stem and progenitor cell defects, the dominant clinical phenotype is severe anemia. In ~60% of patients with DBA, the anemia responds to corticosteroids. However, these responses are often time limited, and steroid-related complications are common, leaving an unmet need for an effective and safe oral therapy. In DBA, ribosomal haploinsufficiency leads to slowed translation and impaired protein synthesis. Globin synthesis is significantly slowed, whereas the production of heme, which requires a small amount of protein because it is synthesized enzymatically, proceeds at a near normal rate. This results in an excess of intracellular heme in early erythroblasts, elevated reactive oxygen species, and other heme-induced toxicity. Bitopertin, an oral competitive inhibitor of glycine import, has been shown to reduce heme synthesis and to have an excellent safety profile in unrelated phase 2 and 3 studies. We reasoned that bitopertin might help balance heme synthesis with globin synthesis and improve erythropoiesis in patients with DBA. Our observations in samples from patients with DBA, CD34+ cells engineered to downregulate RPS19, and a murine DBA model support this concept, justify ongoing clinical studies, and provide insight into optimal trial design.
    DOI:  https://doi.org/10.1016/j.brci.2025.100010
  12. Bone Marrow Transplant. 2026 May 27.
    Outcomes of mixed phenotype acute leukemia undergoing allogeneic stem cell transplantation: a retrospective study of the ALWP of EBMT.
    Annalisa Paviglianiti, Maud Ngoya, Regis Peffault de la Tour, Thomas Schroeder, Peter Remenyi, Linde Morsink, Jaime Sanz, Ladislav Sopko, Francis Ayuk, Mareike Verbeek, Mareike Durholt, Tessa Kerre, Matthias Eder, Pavel Zak, Ibrahim Yakoubagha, Pascal Turlure, Mieke W H Roeven, Alexander Kulagin, Alessandro Maggi, Ron Ram, Alessandro Busca, Werner Rabitsch, Dominik Schneidawind, Eolia Brissot, Fabio Ciceri.
      Limited data is available on outcomes of mixed phenotype acute leukemia (MPAL) following allogeneic stem cell transplantation (HCT), and the impact of haploidentical HCT with post-transplant cyclophosphamide in this setting is lacking. We retrospectively analyzed 195 adults with MPAL undergoing HCT in first complete remission from 2014 to 2023. The 2-year overall survival (OS) and leukemia free survival (LFS) were 70.7% and 56.4%. Relapse incidence (RI) was 29.8% and non-relapse mortality was 13.8% at 2 years. The cumulative incidence of grade II-IV and III-IV acute graft versus host disease (GvHD) was 28.8% and 9.3% at 100 days. The 2-year cumulative incidence of chronic GvHD was 36.6%. The 2-year GvHD-free-relapse free survival was 37.6% (95%CI 29.9-45.3%). In multivariate analysis, patients undergoing myeloablative conditioning had better OS (HR 0.5, 95%CI 0.27-0.93, p = 0.03) and LFS (HR 0.49, 95%CI 0.26-0.94, p = 0.03). The use of peripheral blood was associated with better LFS (HR 0.36, 95%CI 0.17-0.76, p = 0.008) and lower RI (HR 0.33, 95%CI 0.12-0.93, p = 0.04). In vivo T-cell depletion was associated with lower incidence of chronic GvHD (HR 0.32, 95%CI 0.17-0.63, p < 0.001). These findings highlight that conditioning intensity, graft source, and T-cell depletion strategies are critical factors in optimizing transplant outcomes for MPAL.
    DOI:  https://doi.org/10.1038/s41409-026-02920-2
  13. iScience. 2026 Jun 19. 29(6): 115987
    LDLRAD2 drives glycolysis and angiogenesis to promote extramedullary infiltration in acute myeloid leukemia.
    Kexin Jin, Yang Zhao, Qiang Guo, Jingyi Lin, Hongli Zhao, Shengjin Fan, Chuiming Jia, Shuchuan Liu, Desheng Kong.
      Acute myeloid leukemia (AML) remodels the bone marrow microenvironment and can spread to extramedullary sites, a feature associated with adverse clinical outcomes. Here, we identify low-density lipoprotein receptor class A domain-containing 2 (LDLRAD2) as a driver of extramedullary infiltration (EMI) through analyses of patient samples, public datasets, AML cell models, and xenografts. LDLRAD2 increased glucose consumption, lactate production, endothelial tube formation, spleen infiltration, and microvascular density, whereas its knockdown reduced these phenotypes. Mechanistically, LDLRAD2 interacted with metadherin (MTDH) and activated PI3K/AKT/mTOR signaling, thereby promoting glycolysis, angiogenesis, and EMI. Inhibition of LDLRAD2 or treatment with 2-deoxyglucose suppressed glycolysis-associated angiogenic effects. These findings support LDLRAD2-associated metabolic and angiogenic remodeling as a mechanism underlying EMI in AML and highlight a potential therapeutic vulnerability.
    Keywords:  Biochemistry; Health sciences; Pathology
    DOI:  https://doi.org/10.1016/j.isci.2026.115987
  14. J Biol Chem. 2026 May 28. pii: S0021-9258(26)02082-X. [Epub ahead of print] 113210
    Dysregulated HELLS expression alters cellular processes and serves as a potential prognostic marker in acute myeloid leukemia.
    Swati Madhulika, T Sayamsmruti Panda, Priyanka Samal, Sreelakshmi S Kumar, Smrutishree Mohanty, Monalisa Ghosh, Sohini Chakraborty, Asima Das, Jyochnamayi Panda, Subha Saha, Mrutyunjaya Padhy, Tareni Prasad Mallick, Preeti Pranjya Mohapatra, Punit Prasad.
      Spatiotemporal gene expression is regulated by the SNF2 family of ATPases that remodel chromatin, among which helicase lymphoid-specific (HELLS) play an essential role in DNA-templated processes. Analysis from cancer databases revealed HELLS upregulation in several cancers, including acute myeloid leukemia (AML). Using an in vitro myeloid differentiation model, we found that HELLS deficiency promotes myeloid differentiation, apoptosis, cell-cycle arrest, and chromatin instability. Furthermore, HELLS deficiency enhanced myeloid differentiation and apoptosis in HL-60 cells when treated with chemotherapy drugs, including 5-azacytidine, cytarabine, and doxorubicin. Epigenetically, loss of HELLS reduced active histone mark (H3K4me3) and enhanced repressive promoter (H3K27me3), active enhancer (H3K27ac) marks, and chromatin accessibility. Transcriptomic analysis of BeatAML data and bioinformatics analysis revealed that HELLS upregulation is associated with adverse prognosis, as defined by the ELN-2017 classification, and significantly poorer survival. Classification of AML patients into HELLSHigh and HELLSLow gene-expression groups showed that lower HELLS expression was associated with a favorable prognosis and improved remission. HELLS upregulation was positively and negatively associated with leukemic stem/progenitor cell (LSPC) markers and myeloid lineage markers, respectively. Ex vivo validation in AML patient-derived LSPCs demonstrated that HELLS deficiency reduces leukemic marker burden (CD123 and TIM-3) and increases apoptosis. Overall, we show HELLS upregulation drives leukemogenesis with poor outcomes, highlighting its potential as a prognostic marker and therapeutic target in AML.
    Keywords:  AML; Apoptosis; Differentiation; Epigenetics; HELLS
    DOI:  https://doi.org/10.1016/j.jbc.2026.113210
  15. Am J Hematol. 2026 May 29.
    Distinct Longitudinal Patterns of Basal and Squamous Cell Carcinoma in Polycythemia Vera and Essential Thrombocythemia.
    Giuseppe G Loscocco, Naseema Gangat, Paola Guglielmelli, Animesh Pardanani, Alessandro M Vannucchi, Ayalew Tefferi.
      
    Keywords:   TET2 ; basal cell carcinoma; competing‐risk analysis; myeloproliferative neoplasms; non‐melanoma skin cancer; squamous cell carcinoma
    DOI:  https://doi.org/10.1002/ajh.70393
  16. Nat Cell Biol. 2026 May 25.
    A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells.
    Esther Rodríguez-Correa, Florian Grünschläger, Tamar Nizharadze, Natasha Anstee, Jude Al-Sabah, Vojtech Kumpost, Anastasia Sedlmeier, Congxin Li, Melanie Ball, Foteini Fotopoulou, Jeyan Jayarajan, Ian Ghezzi, Julia Knoch, Megan Druce, Kleo Aurich, Marleen Büchler-Schäff, Susanne Lux, Pablo Hernández-Malmierca, Julius Gräsel, Dominik Vonficht, Marta López-Osias, Elvira González-Saiz, Daniel Fernández-Pérez, Anna Mathioudaki, Judith Zaugg, Alejo Rodríguez-Fraticelli, Ralf Mikut, Andreas Trumpp, Thomas Höfer, Daniel Hübschmann, Simon Haas, Michael D Milsom.
      Haematopoietic stem cells (HSCs) display extensive molecular and functional heterogeneity. However, a cohesive model that explains the relationship and biological relevance of these diverse HSC states remains elusive. Here, by performing single-cell transplantations of over 1,000 highly purified murine long-term HSCs combined with in-depth phenotyping of their clonal progeny, we define kinetics-based reconstitution parameters which aligned HSCs into a single hierarchical trajectory reflective of functional potency. This approach revealed that previously identified lineage biases are actually transitory states along this linear trajectory, not a discrete stable condition. Single-cell secondary transplantations validated hierarchical ordering based on reconstitution kinetics, whereas mathematical modelling combined with experimental modulation of lineage-biased blood production revealed that apparent lineage-biased outputs actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to fill mature lineages to their compartment size limit. This study reconciles multiple layers of HSC heterogeneity into a unifying framework.
    DOI:  https://doi.org/10.1038/s41556-026-01958-0
  17. Haematologica. 2026 May 28.
    Real-world heterogeneity in the prognostic value of pre-transplant flow cytometry measurable residual disease in acute myeloid leukemia in first complete remission: CIBMTR analysis.
    Jesse M Tettero, Mei-Jie Zhang, Wentong Liu, Mariam T Nawas, Filippo Milano, Nelli Bejanyan, Veronika Bachanova, Larisa Broglie, Wael Saber, Gege Gui, Laura W Dillon, Roland B Walter, Kristin M Page, Christopher S Hourigan, Firas El Chaer.
      In this real-world, large, observational study from the Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the association between pre-transplant measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) test results and outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). We included 2,544 patients who underwent transplant during 2013-2019; 11% had detectable MRD prior to alloHCT. Patients' median age was 58 years. Among MRD-negative and MRD-positive groups, 48% vs 52% received myeloablative conditioning, and 37% vs 29% had matched unrelated donors, respectively. The 1-year cumulative incidence of relapse was 35% in the MRD-positive group and 25% in the MRD-negative group (P < .001). MRD positivity was associated with inferior overall survival (hazard ratio [HR], 1.27; 95% CI, 1.06-1.51; P = .009) and disease-free survival (HR, 1.31; 95% CI, 1.11-1.53; P = .001), and increased relapse risk (HR, 1.42; 95% CI, 1.17-1.72; P < .001), but not with non-relapse mortality. Notably, patients with pre-alloHCT MRD negativity remained at high risk of relapse, underscoring the limited prognostic utility of registryreported MFC-MRD testing due to variability in methods and thresholds. Survival analyses across the 12 largest centers demonstrated substantial variability in the prognostic impact of MRD. These findings underscore that although pre-alloHCT MRD by MFC remains a clinically relevant prognostic biomarker, its reliability is contingent upon methodological standardization across centers. These findings highlight the need for standardized MRD assessment to improve risk stratification in AML.
    DOI:  https://doi.org/10.3324/haematol.2026.300764
  18. Cell Rep. 2026 May 28. pii: S2211-1247(26)00527-9. [Epub ahead of print]45(6): 117449
    Enhanced formaldehyde clearance ameliorates differentiation-induced genotoxicity in Fanconi anemia mutant cells.
    Jinghang Wu, Fan Yang, Xiaotong Du, Siqian Shi, Landing Li, Zhilin Wang, Jiayi Wang, Can Yi, Yuejia Duan, Yajing Xiao, Sirui Cheng, Xianghuijun Yin, Xinxin Wang, Jianping Jin, Shixian Lin, Liangyu Zheng, Lei Li.
      Fanconi anemia (FA) is a genetic disorder characterized by aplastic anemia and bone marrow failure arising from DNA crosslinking repair deficiencies. During hematopoietic differentiation, formaldehyde accumulates as a byproduct of transcriptional reprogramming, generating DNA crosslinks that abort differentiation and progressively deplete the hematopoietic hierarchy in the absence of FA pathway function. We performed a systematic screen of the aldehyde dehydrogenase (ALDH) activities to identify enzymes capable of metabolizing endogenous formaldehyde and protecting hematopoiesis in FA mutant cells. Our results identify ALDH8A1 as an effective enzyme that ameliorates formaldehyde-induced DNA damage during hematopoietic differentiation. Enhanced formaldehyde clearance significantly reduces DNA damage, markedly improving the survival of differentiating FA mutant progenitor cells and enabling completion of lineage progression. These findings highlight enhanced formaldehyde metabolism as an effective approach to ameliorate endogenous genotoxicity in FA mutant blood cells, suggesting a potential therapeutic strategy for restoring sustained hematopoiesis in patients with FA.
    Keywords:  CP: Cancer; CP: Cell biology; DNA damage; Fanconi anemia; aldehyde dehydrogenases; formaldehyde clearance; hematopoiesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117449
  19. Blood Adv. 2026 May 27. pii: bloodadvances.2025019525. [Epub ahead of print]
    Clinical Heterogeneity and Outcome of acquired PRCA: a Multicenter European Study.
    Francesco Versino, Marc Michel, Jennifer Vidler, Salvador Payán-Pernía, Roochi Trikha, Shreyans A Gandhi, Sukanya Gogoi, Manujasri Wimalachandra, Omar Racchi, Maria Teresa Lupo-Stanghellini, Sabrina Giammarco, Maria Arguello Marina, Mara Memoli, Andreas Glenthøj, Gabriele Merati, Yamuna Wasanthi Wickramasinghe, Aparna Chitharanjan, Mylene Hemmer, Mariasanta Napolitano, Margarita Jimenez-Jambrina, Filippo Brioschi, Antonio Palma-Vallelano, Tomas Jose Gonzalez-Lopez, Cristina Clissa, Marta Bortolotti, Giacinto Luca Pedone, Giorgio Alberto Croci, Francesco Passamonti, Wilma Barcellini, Austin G Kulasekararaj, Bruno Fattizzo.
      Pure red cell aplasia (PRCA) is a rare single lineage bone marrow failure defined by anemia with profound reticulocytopenia and severe reduction of erythroid precursors. Clinical spectrum is heterogeneous, and diagnosis often requires extensive evaluation to distinguish primary from secondary causes such as thymoma, autoimmune diseases, T-LGL expansion and MDS, with which differential diagnosis is particularly challening. Evidence guiding management remains limited due to the rarity of the disease and the lack of prospective studies. We conducted a multicenter retrospective analysis of 121 acquired adult PRCA (excluding PVB19-associated PRCA) cases across 14 European centers. Secondary forms accounted for 78% of cases, mostly thymoma (23%) or MDS (21%). In a subset of patients, BM immunohistochemistry demonstrated significant depositions of C3, C4d, IgM, IgG, reducing after immunosuppression. NGS was performed in half of patients 36% of which presented mutations predominantly related to clonal hematopoiesis, except in MDS-associated cases which often carried multiple non-CH mutations. Immunosuppression represented the backbone of therapy: cyclosporine A (CyA) was the most effective agent, with 61% ORR (47% complete) and better outcomes when initiated earlier; mTOR inhibitors showed promising activity as second-line therapy, with responses in 71% of patients, including CyA-refractory cases. Mortality reached 30%, predominantly due to infectious complications, and was significantly higher in MDS-associated cases. PRCA remains a diagnostically challenging and clinically heterogeneous disorder in which integration of molecular analyses may refine diagnostic accuracy and patient stratification. Immunosuppression remains the mainstay of treatment, with CyA being a reliable first-line and mTORi emerging as encouraging rescue options.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019525
  20. Blood Cancer J. 2026 May 28.
    Chronic myeloid leukemia: incorporation of recent advances into current treatment algorithms.
    Fadi G Haddad, Hagop Kantarjian.
      Several approved and investigational BCR::ABL1 tyrosine kinase inhibitors (TKIs) and STAMP inhibitors are used for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). In the frontline setting, multiple factors affect selection of therapy including the goal of treatment, cost of TKIs, CML risk, and patient's comorbidities. Achieving a complete cytogenetic response (BCR::ABL1 transcripts on the International Scale [IS] <1%) with TKI therapy within the first year is associated with normalization of survival, whereas achieving a deeper molecular response (BCR::ABL1 transcripts < 0.01% [IS]) may allow for treatment discontinuation with the possibility of treatment-free remission. Although standard doses are approved for each TKI, post approval studies have demonstrated that an optimal biologic dose is safer than and as effective as the approved dose. In cases of TKI toxicities, reducing the dose rather than switching TKIs is recommended unless the patient experiences a prohibitive toxicity, in which case the treatment should be changed. In patients experiencing failure of frontline therapy due to resistance or intolerance, multiple second- and third-line options are available, including second-generation TKIs, ponatinib, and asciminib, as well as novel investigational agents, including the ABL1 kinase domain inhibitors olverembatinib and ELVN-001 and the STAMP inhibitors TGRX-678 and TERN-701. In this review, we discuss the recent advances in the treatment of CML-CP and challenge some established management practices.
    DOI:  https://doi.org/10.1038/s41408-026-01527-6
  21. Am J Hematol. 2026 May 26.
    Characteristics and Prognostic Implications in Newly Diagnosed KMT2Ar AML: A Multicenter Study of the ECLA Group.
    East China Leukemia Alliance
      Acute myeloid leukemia (AML) harboring KMT2A rearrangement (KMT2Ar) was generally associated with poor prognosis. We enrolled 490 patients with KMT2Ar from the East China Leukemia Alliance between March 2013 and August 2025. KMT2A::MLLT3 was the most frequent KMT2Ar (31.6%), followed by KMT2A::MLLT4 (25.1%), KMT2A::ELL (20%), and KMT2A::MLLT10 (12.7%). KMT2A::MLLT4 showed an inferior prognosis. The most co-occurring gene mutations were KRAS (20.1%), NRAS (19.0%), TET2 (10.2%), WT1 (8.6%), and PTPN11 (7.4%). Trisomy 8 was more common in patients < 60 years, while FLT3-ITD was only detected in patients < 60 years. With a median follow-up time of 42.6 months, the median overall survival (OS) of all patients was 30.9 months, and the 3-year OS rate was 49.9%. Patients treated with venetoclax plus intensive chemotherapy (Ven+IC) showed the best composite complete remission (CRc) rate and OS compared to intensive chemotherapy, venetoclax plus reduced-intensive chemotherapy, and reduced-intensive chemotherapy (CRc rate: 89.5% vs. 62.4% vs. 57.3% vs. 61.4%; median OS: not reached vs. 39.9 months vs. 34.8 months vs. 12.7 months). Multivariate analysis identified multiparameter flow cytometry minimal residual disease negativity post-induction therapy, allogeneic hematopoietic stem cell transplantation, and Ven+IC as independent favorable prognostic factors for event-free survival (EFS), and KMT2A::MLLT4 fusion, EVI1 overexpression were independent unfavorable prognostic factors for EFS. In summary, our study showed characteristics and prognostic implications in newly diagnosed KMT2Ar AML in China.
    DOI:  https://doi.org/10.1002/ajh.70377
  22. Br J Haematol. 2026 May 29.
    Further insights into the application of the TFR prognostic score (TPS) in CML patients attempting TFR.
    Simone Claudiani, Silvia Metelli, Dragana Milojkovic.
      
    DOI:  https://doi.org/10.1111/bjh.70571
  23. Br J Haematol. 2026 May 28.
    Outcomes of patients with de novo and secondary acute myeloid leukaemia treated with front-line hypomethylating agents and venetoclax: A retrospective Italian study.
    Ilaria Tanasi, Edoardo Tamellini, Elena Marchetti, Eleonora De Bellis, Cristina Ancora, Francesco Angotzi, Davide Facchinelli, Francesca Capraro, Giulia Battaglia, Alessandra Sperotto, Michele Gottardi, Matteo Leoncin, Mauro Krampera, Mario Tiribelli, Carmela Gurrieri.
      
    Keywords:  leukaemia; secondary acute myeloid leukaemia; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70587
  24. Haematologica. 2026 May 28.
    Next generation sequencing-based measurable residual disease detection predicts outcomes in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.
    Simon M Krauß, Tara Holloway, Anne Weigert, Lara Bischof, Donata Backhaus, Dominic Brauer, Jule Ussmann, Georg-Nikolaus Franke, Vladan Vučinić, Uwe Platzbecker, Sebastian Schwind, Madlen Jentzsch, Klaus H Metzeler.
      Sensitive, scalable and affordable measurable residual disease (MRD) assays are needed to guide treatment decisions in acute myeloid leukemia (AML), particularly around allogeneic hematopoietic stem cell transplantation (allo-SCT). Next-generation sequencing (NGS)-based MRD assays offer broad applicability and high sensitivity, but remain too costly for routine use in resource-limited environments. We developed a cost-efficient, sensitive NGS MRD assay utilizing single-molecule molecular inversion probes (smMIPs) targeting 92 genomic loci in 33 AML driver genes and applied it to 93 AML patients in remission prior to allo-SCT. MRD positivity, defined as the presence of ≥ 1 non-DTA (DNMT3A, TET2, ASXL1) gene variant with ≥ 0.5% variant allele frequency (VAF), was associated with significantly shorter post-transplantation overall survival (OS; p < 0.001). In multivariable analysis, NGS-based MRD detection remained an independent predictor of inferior OS (hazard ratio 4.58; p = 0.002). Conditioning intensity did not associate with outcome of MRD-positive patients in this retrospective cohort. Mutations at diagnosis and pretransplantation showed variable concordance across genes, and consistently lower VAFs at the later timepoint. In three patients, multiple low-VAF clustered variants in RUNX1 and TET2 were detected pre-transplantation, potentially indicating treatment-induced mutagenesis. These findings demonstrate that a broadly applicable, smMIP-based NGS MRD assay can provide clinically relevant risk stratification before allo-SCT in AML, while its low library preparation costs of approximately 8€ per sample may facilitate wide implementation in routine practice and allow more patients to receive MRD-directed therapeutic interventions.
    DOI:  https://doi.org/10.3324/haematol.2025.300432
  25. Haematologica. 2026 May 28.
    Lorlatinib-induced remission in refractory acute myeloid leukemia with an anaplastic lymphoma kinase fusion.
    Leora Boussi, Natalia Tijaro Ovalle, Brandon S Imber, Mark D Ewalt, Michael Glick, Brian Shaffer, Eytan M Stein.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300893
  26. Nat Cancer. 2026 May 25.
    Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
    Alan Y L Wong, Jacob W Myers, Gyan Prakash, Alice Ma, Jeannette R Brook, Boryana Petrova, Baran Bulut, Ralph White, Catherine Merz, Maeve de Souza, Adam G Maynard, Peng Wang, Amy Yu, Nancy K Pohl, Michal Weitman, Lewis B Silverman, Kimberly Stegmaier, L Stirling Churchman, Peter D Cole, Donita C Brady, Naama Kanarek.
      The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.
    DOI:  https://doi.org/10.1038/s43018-026-01177-4
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