bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–08–31
25 papers selected by
William Grey, University of York
  1. Alteration of long- and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis.
  2. TLR2 Agonism Suppresses Myeloid Leukemogenesis by Reprogramming Leukemia Stem Cells.
  3. Haematopoietic stem cell number is not solely defined by niche availability.
  4. Mapping Hematopoietic Fate after Transplantation.
  5. Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia.
  6. Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
  7. Ex-vivo Expansion of Cord Blood Hematopoietic Stem Cells in Serum-Free Medium with Feeder Layer - A New Hope for Successful Cord Blood Transplantation in Adults.
  8. Cells prioritize the regulation of cell mass density.
  9. Mesenchymal stromal cells from JAK2 V617F myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.
  10. Leukemic Cells Hijack Stromal Bioelectricity to Reprogram the Bone Marrow Niche via CaV1.2-Dependent Mechanisms.
  11. The long non-coding RNA CRNDE stabilises SIRT1 protein and influences Hedgehog signalling in multiple myeloma.
  12. Signature of leukemia stem cell death pattern predicts prognosis and therapeutic response of acute myeloid leukemia patients.
  13. Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
  14. Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
  15. LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.
  16. Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.
  17. Haematopoietic ageing in health and lifespan.
  18. Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia.
  19. The bispecific innate cell engager AFM28 eliminates CD123+ leukemic stem and progenitor cells in AML and MDS.
  20. α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
  21. Image-based drug screening combined with molecular profiling identifies signatures and drivers of therapy resistance in pediatric AML.
  22. SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.
  23. Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation.
  24. The instrumental role of lipids in governing the sensitivity of multiple myeloma to ferroptosis.
  25. A protein tunnel helps stressed lysosomes swell.
  1. Elife. 2025 Aug 27. pii: RP95880. [Epub ahead of print]13
    Alteration of long- and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis.
    Katsuyuki Nishi, Taro Sakamaki, Akiomi Nagasaka, Kevin Shuolong Kao, Kay Sadaoka, Masahide Asano, Nobuyuki Yamamoto, Akifumi Takaori-Kondo, Masanori Miyanishi.
      Myeloid-biased hematopoiesis is a well-known age-related alteration. Several possibilities, including myeloid-biased hematopoietic stem cell (HSC) clones, may explain this. However, the precise mechanisms remain controversial. Utilizing the Hoxb5 reporter system to prospectively isolate long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs), we found that young and aged LT-HSCs co-transplanted into the same recipients demonstrated nearly equivalent myeloid lineage output, contrary to the theory of myeloid-biased HSC clones. Transcriptomics indicated no significant myeloid gene enrichment in aged LT-HSCs compared to their young counterparts. Instead, transplanting reconstituted young HSCs with the ratio of LT/ST-HSCs seen in aged mice can significantly skew the lineage output to myeloid cells. In addition, while the niche environment in the bone marrow minimally affects myeloid-biased hematopoiesis, aged thymi and spleens substantially hinder lymphoid hematopoiesis, resulting in further myeloid domination. Thus, we demonstrate that myeloid-biased hematopoiesis in aged mice originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.
    Keywords:  aging; developmental biology; long-term hematopoietic stem cell; mouse; myeloid bias; regenerative medicine; self-renewal; short-term hematopoietic stem cell; stem cells
    DOI:  https://doi.org/10.7554/eLife.95880
  2. Blood Adv. 2025 Aug 20. pii: bloodadvances.2025017018. [Epub ahead of print]
    TLR2 Agonism Suppresses Myeloid Leukemogenesis by Reprogramming Leukemia Stem Cells.
    Michael E Lawler, Jennifer S Romer-Seibert, Michael S Bowman, Ramkrishna Mitra, Christine M Eischen, Robert L Bowman, Sara E Meyer.
      The consequences of activated innate immune signaling in acute myeloid leukemia (AML) is not well understood. Using ligands directed at the Toll-like family receptors (TLR) in models of high-risk AML, we uncover that TLR2 ligands exert unique anti-leukemic effects that are distinct from other TLRs. While TLR2 signaling broadly induces inflammatory gene expression in AML cells, at the single cell level, cell-type-dependent, divergent transcriptional responses coordinate cellular outputs of proliferation, differentiation, cell death, and activation of immune cell function. TLR2 ligands were the only TLR agonists capable of extending survival of AML-bearing mice through leukemia stem cell (LSC) reprogramming that elevated MHC class II surface expression and ultimately impaired self-renewal. We find that the co-expression of TLR2 and MHCII genes is associated with better overall survival in AML patients, which is consistent with our observations of activated TLR2 signaling in mice. These data reveal functional TLR2 signaling critically antagonizes leukemogenesis and emphasizes a role for TLR2 agonism in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017018
  3. Nature. 2025 Aug 27.
    Haematopoietic stem cell number is not solely defined by niche availability.
    Shoichiro Takeishi, Tony Marchand, Wade R Koba, Daniel K Borger, Chunliang Xu, Chandan Guha, Aviv Bergman, Paul S Frenette, Kira Gritsman, Ulrich Steidl.
      Haematopoietic stem cells (HSCs) reside in specialized microenvironments, referred to as niches, and the classical model suggests that HSC numbers are predominantly determined by the niche size1-5. However, the vast excess of niche cells relative to HSCs challenges this perspective. To rigorously define the role of niche size in regulating HSC numbers, we developed a femur-transplantation system, enabling us to increase available HSC niches. Notably, the addition of niches did not alter the total HSC numbers in the body, suggesting the presence of a systemic mechanism that limits HSC numbers. Additionally, HSC numbers in transplanted wild-type femurs did not exceed physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are constrained at the local level as well. The notion of dual restrictions at systemic and local levels was further supported by other experimental approaches, including parabiosis and non-conditioned transfer of HSCs after bone transplantation. Moreover, we found that thrombopoietin has a pivotal role in determining the total number of HSCs in the body, even in the context of increased niche availability. Our study redefines key principles underlying HSC number regulation, providing insights into this critical biological process.
    DOI:  https://doi.org/10.1038/s41586-025-09462-5
  4. Stem Cell Rev Rep. 2025 Aug 20.
    Mapping Hematopoietic Fate after Transplantation.
    Stephanie N Hurwitz.
      Hematopoietic stem and progenitor cells (HSPCs) form the foundation of lifelong blood cell production and immune function. Understanding their fate, including how they differentiate, self-renew, and respond to environmental cues has long been a cornerstone of stem cell biology and regenerative medicine. This knowledge is especially vital in the context of therapeutic hematopoietic stem and progenitor cell transplantation, where the diverse behavior of transplanted HSPCs directly impacts patient outcomes. Advances in single-cell omics, lineage barcoding, and in situ tracking now allow us to directly trace the developmental trajectories and clonal contributions of individual HSPCs. These tools are reshaping our understanding of hematopoiesis not as a rigid hierarchy but as a dynamic and adaptive system. This review highlights key technologies that enable fate mapping of HSPCs, integrates insights into clonal behavior during both transplantation and native hematopoiesis, and discusses how these findings are likely to inform future diagnostic and therapeutic strategies. CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Barcoding; Clonal Mapping; Hematopoiesis; Hematopoietic Stem Cells; Single-cell; Transplantation
    DOI:  https://doi.org/10.1007/s12015-025-10946-0
  5. Leukemia. 2025 Aug 26.
    Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia.
    Rita Hleihel, Hala Skayneh, Hsin-Chieh Wu, Maguy Hamie, Abdallah Kurdi, Jana Dakour, Charbel Machaalani, Marwan El-Sabban, Hugues de Thé, Ali Bazarbachi, Hiba El Hajj.
      Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients' blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.
    DOI:  https://doi.org/10.1038/s41375-025-02731-2
  6. Science. 2025 Aug 21. eadr8785
    Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
    Benjamin Furtwängler, Nil Üresin, Sabrina Richter, Mikkel Bruhn Schuster, Despoina Barmpouri, Henrietta Holze, Anne Wenzel, Kirsten Grønbæk, Kim Theilgaard-Mönch, Fabian J Theis, Erwin M Schoof, Bo T Porse.
      Single-cell transcriptomics (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leveraged recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins that are important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multi-omics studies across biological systems.
    DOI:  https://doi.org/10.1126/science.adr8785
  7. Int J Hematol Oncol Stem Cell Res. 2025 Apr 01. 19(2): 165-179
    Ex-vivo Expansion of Cord Blood Hematopoietic Stem Cells in Serum-Free Medium with Feeder Layer - A New Hope for Successful Cord Blood Transplantation in Adults.
    Asmaa M Borg, Fatma Auf, Farha El-Chennawi, Zakaria F Lotfy.
      Background: Umbilical cord blood is widely regarded as a viable option for allogeneic hematopoietic stem cell transplantation (HSCT) and serves as a potential alternative to bone marrow due to its numerous advantages. These include a non-invasive collection process, a high concentration of hematopoietic stem and progenitor cells, and a lower risk of graft rejection. However, its application in adult patients is limited by the suboptimal dose of stem cells available in a single umbilical cord blood unit. This insufficient cell dose increases the risk of engraftment failure and post-transplant mortality, posing a significant challenge for its use in adult populations. Materials and Methods: This study aims to develop a protocol for expanding umbilical cord blood mononuclear cells (UCB-MNCs) using a serum-free culture medium called StemSpan, supplemented with a mesenchymal stem cell (MSC) feeder layer and a combination of growth factors. The growth factors used include stem cell factor (SCF), thrombopoietin (TPO), fibroblast growth factor-1 (FGF-1), and heparin. The expansion culture was applied to 20 UCB samples and maintained over a period of 13 days. Data collected from the experiments were analyzed using the SPSS program (Statistical Package for the Social Sciences) for Windows, version 21. Results: The protocol led to a notable increase in the viable mononuclear cell counts, the absolute hematopoietic stem and progenitor cell counts, and the clonogenic progenitors. Conclusion: This designed protocol could support the expansion of the umbilical cord blood mononuclear cells, including hematopoietic stem and progenitor cells, which could provide hope for better engraftment in adult patient transplantations. The designed protocol could effectively promote the expansion of umbilical cord blood mononuclear cells, particularly hematopoietic stem and progenitor cells. This advancement offers promising potential for improving engraftment outcomes in adult patient transplantations.
    Keywords:  Ex-vivo expansion; Hematopoietic stem cells; Mesenchymal stem cells; Progenitor cells
    DOI:  https://doi.org/10.18502/ijhoscr.v19i2.18554
  8. Sci Adv. 2025 Aug 29. 11(35): eadv9759
    Cells prioritize the regulation of cell mass density.
    Jinyu Fu, Qin Ni, Yufei Wu, Anoushka Gupta, Zhuoxu Ge, Hongru Yang, Yasin Afrida, Ishan Barman, Sean X Sun.
      A cell's global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume defines the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the fluorescence eXclusion method (FXm) and quantitative phase microscopy (QPM), we investigate CMD dynamics following sudden changes in media osmolarity. We find that while cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery over 48 hours. This recovery is cell cycle independent and depends on coordinated adjustment of protein synthesis and volume growth rates. Unexpectedly, the protein synthesis rate decreases when CMD increases. We observe that nucleoplasm-cytoplasm transport is CMD dependent, which contributes to negative regulatory feedback on CMD. The Na+/H+ exchanger helps regulate CMD by affecting both protein synthesis and volume change. Together, we reveal that cells have a robust control system that actively regulates CMD during environmental change.
    DOI:  https://doi.org/10.1126/sciadv.adv9759
  9. Hemasphere. 2025 Aug;9(8): e70185
    Mesenchymal stromal cells from JAK2 V617F myeloproliferative neoplasms support healthy and malignant hematopoiesis in a humanized scaffold model in vivo.
    Alessandra Ferrelli, Syed Mian, Marion Piganeau, Hector Huerga Encabo, Despoina Papazoglou, Giuseppe D'Agostino, Fatihah Mohamad Nor, Manuel Garcia-Albornoz, Steven Ngo, Linda Ariza-McNaughton, Erika Morsia, Matteo Giovanni Della Porta, Claire Harrison, Shahram Kordasti, Dominique Bonnet.
      Myeloproliferative Neoplasms (MPN) are malignancies of hematopoietic stem and progenitor cells (HSPCs) that lead to the overproduction of mature blood cells. These disorders include Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), primarily driven by somatic mutations such as JAK2 V617F . Research indicates that mesenchymal stromal cells (MSCs) support fibrosis in PMF, though their role in ET and PV remains less clear. Furthermore, in vivo studies of ET/PV HSPCs remain a challenge due to low engraftment levels in xenograft models. We employed a 3D scaffold model to create an MPN humanized xenograft mouse model, enabling in vivo functional studies of primary MPN progenitor cells and the supportive role of human MSCs. Using this model, we first demonstrated robust hematopoietic support of healthy (HD) HSPCs by PV and ET MSCs. We then investigated the role of MSCs in sustaining JAK2 V617F mutant cells by using a CRISPR-Cas9 editing model, along with primary PV and ET HSPCs. Our results showed consistent engraftment of CRISPR-edited JAK2 V617F mutant HSPCs and PV and ET patient-derived HSPCs in scaffolds seeded with HD, PV, and ET stroma, providing the first in vivo evidence that PV and ET MSCs can sustain both healthy and MPN-associated hematopoiesis. Furthermore, HD MSCs were also capable of sustaining PV and ET HSPCs in vivo. Overall, we present the first humanized MPN xenograft model that offers valuable insights into how human BM MSCs interact with JAK2 V617F mutant clones.
    DOI:  https://doi.org/10.1002/hem3.70185
  10. Adv Sci (Weinh). 2025 Aug 20. e08940
    Leukemic Cells Hijack Stromal Bioelectricity to Reprogram the Bone Marrow Niche via CaV1.2-Dependent Mechanisms.
    Ambra Da Ros, Maddalena Benetton, Giulia Borella, Giorgia Longo, Giulia Borile, Alice Cani, Diego Lopez-Pigozzi, Mario Bortolozzi, Silvia Bresolin, Claudia Tregnago, Franco Locatelli, Martina Pigazzi.
      Mesenchymal stromal cells (MSCs) are key components of the tumor microenvironment (TME), influencing leukemia progression through poorly understood mechanisms. Here, the bioelectrical properties of MSCs derived from pediatric acute myeloid leukemia (AML) patients (AML-MSCs) are investigated, identifying a significant depolarization of their resting voltage membrane potential (Vmem, -14.7 mV) compared to healthy MSCs (h-MSCs, -28.5 mV), accompanied by downregulation of Calcium channel, voltage-dependent, L type, alpha 1C subunit1.2 (CaV1.2) L-type calcium channel expression. AML-MSCs display increased spontaneous calcium oscillations, suggesting altered ion homeostasis. Notably, h-MSCs exposed to AML blasts undergo a similar Vmem depolarization (-11.8 mV) and CaV1.2 downregulation, indicating that leukemic cells actively reprogram MSCs. Functionally, Vmem depolarization in h-MSCs promotes a pro-leukemic phenotype, whereas hyperpolarization of AML-MSCs restores a normal behavior. CaV1.2 over-expression by lentiviral vectors in AML-MSCs shifts the Vmem toward hyperpolarization and partially reverses their leukemia-supportive properties, in part through CaV1.2 transfer via tunneling nanotubes. These findings reveal that AML blasts impose a bioelectrical signature on MSCs, modulating ion channel activity to sustain a leukemic niche. Targeting this electrical reprogramming through CaV1.2 restoration represents a potential strategy to re-establish homeostasis in the bone marrow microenvironment.
    Keywords:  acute myeloid leukemia; bioelectricity; mesenchymal stromal cells; tumor microenvironment; voltage membrane potential
    DOI:  https://doi.org/10.1002/advs.202508940
  11. Leukemia. 2025 Aug 26.
    The long non-coding RNA CRNDE stabilises SIRT1 protein and influences Hedgehog signalling in multiple myeloma.
    Simone Zocchi, Pauline Trichet, Paloma Guernalec, Manal Agdada, Ana Alonso Bartolomé, Vincent Ogor, Caroline Choisy, Carine Vias, Xavier Sabaté-Cadenas, Jean-Christophe Bories, Michele Goodhardt, Alena Shkumatava, David Garrick.
      Multiple myeloma (MM) is a malignancy of immunoglobulin-secreting plasma cells that represents 10% of all hematological cancers and remains essentially incurable, despite recent advances. Long non-coding RNAs (lncRNAs) are an important class of regulatory molecules that have been strongly implicated in the aetiology of MM. Colorectal Neoplasia Differentially Expressed (CRNDE) is one lncRNA that is upregulated in tumor plasma cells of MM patients and contributes to disease progression and outcome. In order to characterise the molecular mechanisms of CRNDE action in MM, here we have carried out a high-throughput screen to identify proteins interacting with this lncRNA inside cells. From the output of this screen, we demonstrate that in MM cells, CRNDE interacts with and stabilises the deacetylase protein SIRT1, previously identified as an important mediator of the Hedgehog (Hh) signalling pathway in MM. We further show that CRNDE exerts downstream effects on MM cell survival, tumorigenic potential, and stem-like properties via an effect on the SIRT1/Hh signalling axis. Our findings add to the molecular understanding of the pro-tumorigenic activity of CRNDE in MM and could have wider implications in other malignant diseases.
    DOI:  https://doi.org/10.1038/s41375-025-02736-x
  12. Sci Rep. 2025 Aug 27. 15(1): 31612
    Signature of leukemia stem cell death pattern predicts prognosis and therapeutic response of acute myeloid leukemia patients.
    Fuqiang Wang, Minjie Li, Nan Cui, Qiyue Fu, Fei Li, Zhimin Gu.
      Acute Myeloid Leukemia (AML) is a highly heterogeneous malignant hematologic cancer with poor clinical outcome. The presence of leukemia stem cells (LSC) is a significant factor contributing to the failure of AML treatments and frequent relapses. The quiescent and plastic nature of LSC decreases cell death under conventional chemotherapy. Programmed cell death (PCD) plays a critical role in the development and progression of various cancers including AML. We hypothesized that the expression of PCD gene in LSCs may predict the therapeutic outcome of AML patients in the clinic. In this study, we comprehensively analyzed the expression of PCD gene and identified the unique expression patterns of cell death genes of LSC. By integrating PCD- and LSC-related genes, we identified eight LSC death genes with prognostic values: OAZ1, S100A4, MPG, IL2RA, MMRN1, CDK6, HOXA9, and XIRP2. Based on these genes, we developed a leukemia stem cell prognostic death score (LSCD) and a prognostic nomogram. Our findings revealed that LSC, particularly Quiescent LSPC, exhibits a high LSCD score. AML patients with high LSCD score group showed characteristics of significant immune dysfunction and worse prognosis. Additionally, predictions regarding FDA-approved drugs indicated that the high LSCD score group is less sensitive to Venetoclax but more sensitive to Crenolanib, Tandutinib, or Midostaurin. In summary, we developed an LSCD model that shows the predictive potential of clinical prognosis and drug sensitivity. This model provides meaningful insights for personalized treatment of AML patients.
    Keywords:  Bioinformatics; Drug sensitivity; Leukemia stem cell; Prognosis; Programmed cell death
    DOI:  https://doi.org/10.1038/s41598-025-17288-4
  13. Sci Adv. 2025 Aug 29. 11(35): eady0240
    Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.
    William M Rosencrans, Ryan W Lee, Logan McGraw, Ian Horsburgh, Ting-Yu Wang, Baiyi Quan, Diana Huynh, Jennifer A Johnston, David C Chan, Tsui-Fen Chou.
      The PINK1/Parkin pathway targets damaged mitochondria for degradation via mitophagy. Genetic evidence implicates impaired mitophagy in Parkinson's disease, making its pharmacological enhancement a promising therapeutic strategy. Here, we characterize two mitophagy activators: a novel Parkin activator, FB231, and the reported PINK1 activator MTK458. Both compounds lower the threshold for mitochondrial toxins to induce PINK1/Parkin-mediated mitophagy. However, global proteomics revealed that FB231 and MTK458 independently induce mild mitochondrial stress, resulting in impaired mitochondrial function and activation of the integrated stress response, effects that result from PINK1/Parkin-independent off-target activities. We find that these compounds impair mitochondria by distinct mechanisms and synergistically decrease mitochondrial function and cell viability in combination with classical mitochondrial toxins. Our findings support a model whereby weak or "silent" mitochondrial toxins potentiate other mitochondrial stressors, enhancing PINK1/Parkin-mediated mitophagy. These insights highlight important considerations for therapeutic strategies targeting mitophagy activation in Parkinson's disease.
    DOI:  https://doi.org/10.1126/sciadv.ady0240
  14. Blood. 2025 Aug 26. pii: blood.2025029132. [Epub ahead of print]
    Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.
    Cristiana O'Brien, Nirvana Nursimulu, Anit Tyagi, Rachel Culp-Hill, Andrea Arruda, Tracy Murphy, Mark D Minden, Andrew Kent, Brett M Stevens, Daniel A Pollyea, Kristin Hope, Sushant Kumar, Julie A Reisz, Angelo D'Alessandro, Courtney L Jones.
      Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome. Circulating metabolites are influenced by patients' clinical status and can serve as accessible cancer biomarkers. To establish a resource of circulating metabolites in genetically diverse AML patients, we performed an unbiased metabolomic and lipidomic analysis of 231 diagnostic AML plasma samples prior to treatment with intensive chemotherapy. Intriguingly, circulating metabolites were highly associated with the mutation status within the AML cells. Further, lipids were associated with refractory status. We established a machine learning algorithm trained on chemo-refractory associated lipids to predict patient survival. Cox regression and Kaplan-Meier analysis demonstrated that the high-risk lipid signature predicted overall survival in this patient cohort. Impressively, the top lipid in the high-risk lipid signature, sphingomyelin (d44:1), was sufficient to predict overall survival in the original and an independent validation dataset. Overall, this research underscores the potential of circulating metabolites to capture AML heterogeneity and lipids to be used as potential AML biomarkers.
    DOI:  https://doi.org/10.1182/blood.2025029132
  15. Nat Commun. 2025 Aug 21. 16(1): 7812
    LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.
    Dhanusha A Nalawansha, Georgios Mazis, Gitte Husemoen, Kate S Ashton, Weixian Deng, Ryan P Wurz, Anh T Tran, Brian A Lanman, Jiansong Xie, Robert G Guenette, Shiqian Li, Christopher E Smith, Suresh Archunan, Manoj K Agnihotram, Arghya Sadhukhan, Rajiv Kapoor, Chris Wilde, Sajjan Koirala, Felipe De Sousa E Melo, Patrick Ryan Potts.
      Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRASG12D signaling can be potently inhibited by LYMTACs. Mechanistically, LYMTACs display multi-pharmacology and exert their activity through both target relocalization into the lysosome and degradation. We further generalize LYMTACs across various LMPs and thus offer a platform to access challenging membrane proteins through targeted protein relocalization and degradation.
    DOI:  https://doi.org/10.1038/s41467-025-63128-4
  16. Nat Commun. 2025 Aug 26. 16(1): 7955
    Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.
    Takashi Mikami, Itaru Kato, Akira Nishimura, Minenori Eguchi-Ishimae, Tatsuya Kamitori, Keiji Tasaka, Hirohito Kubota, Tomoya Isobe, Yoshinori Uchihara, Yui Namikawa, Satoru Hamada, Shinichi Tsujimoto, Shotaro Inoue, Takayuki Hamabata, Kazushi Izawa, Takako Miyamura, Daisuke Tomizawa, Toshihiko Imamura, Hidemi Toyoda, Mariko Eguchi, Hiroaki Goto, Seishi Ogawa, Masatoshi Takagi, James Badger Wing, Junko Takita.
      Lineage switching (LS) is the conversion of cancer cell lineage during the course of a disease. LS in leukemia cell lineage facilitates cancer cells escaping targeting strategy like CD19 targeted immunotherapy. However, the genetic and biological mechanisms underlying immune evasion by LS leukemia cells are not well understood. Here, we conduct a multi-omics analysis of patient samples and find that lineage-switched acute myeloid leukemia (LS AML) cells with KMT2A rearrangement (KMT2A-r) possess monocytic myeloid derived suppressor cell (M-MDSC)-like characteristics. Single-cell mass cytometry analysis reveals an increase in the M-MDSC like LS AML as compared to those of lineage-consistent KMT2A-r AML, and single-cell transcriptomics identify distinct expression patterns of immunoregulatory genes within this population. Furthermore, in vitro assays confirm the immunosuppressive capacity of LS AML cells against T cells, which is analogous to that of MDSCs. These data provide insight into the immunological aspects of the complex pathogenesis of LS AML, as well as development of future treatments.
    DOI:  https://doi.org/10.1038/s41467-025-63271-y
  17. Nat Cell Biol. 2025 Aug 25.
    Haematopoietic ageing in health and lifespan.
    Rebecca Andersson, Eva Mejia-Ramirez, Maria Carolina Florian.
      Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism.
    DOI:  https://doi.org/10.1038/s41556-025-01739-1
  18. Leukemia. 2025 Aug 21.
    Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia.
    Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang.
      Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in FLT3-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that FLT3-ITD-positive patients with low p16INK4a expression have significantly worse prognoses. Consistent with these clinical findings, knockout of p16INK4a in mice was shown to accelerate FLT3-ITD AML onset. Mechanistic investigations further revealed that the FLT3-ITD mutation suppresses p16INK4a expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of p16INK4a allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the FLT3-ITD-STAT5A/E2F3/EZH2-p16INK4a axis identified in this study represents a promising therapeutic target for addressing refractory FLT3-ITD AML with low p16INK4a expression.
    DOI:  https://doi.org/10.1038/s41375-025-02743-y
  19. Nat Commun. 2025 Aug 21. 16(1): 7793
    The bispecific innate cell engager AFM28 eliminates CD123+ leukemic stem and progenitor cells in AML and MDS.
    Nanni Schmitt, Jana-Julia Siegler, Alexandra Beck, Thomas Müller, Izabela Kozlowska, Séverine Sarlang, Uwe Reusch, Stefan Knackmuss, José Medina-Echeverz, Joachim Koch, Thorsten Ross, Ali Darwich, Lea Hoppe, Mohammed Abba, Alexander Streuer, Stefan Klein, Wolf-Karsten Hofmann, Anna Lisa Gündner, Christian Merz, Jan Endell, Jens Pahl, Daniel Nowak.
      Strategies targeting leukemic stem and progenitor cells (LSPCs) are needed for durable remissions in acute myeloid leukemia (AML) and high-risk myelodysplastic neoplasms (MDS). While CD123 constitutes a promising target on LSPCs and leukemic blasts, previous CD123-targeting approaches showed limited efficacy and challenging safety profiles. Here, we describe the preclinical efficacy and safety of the bispecific CD123/CD16A innate cell engager "AFM28", demonstrating superior activity against AML and MDS patient-derived LSPCs and blasts in vitro compared to an Fc-enhanced CD123-targeting antibody, especially towards CD123low and/or CD64+ leukemic cells. AFM28 induces autologous anti-leukemic activity in fresh AML whole blood cultures, demonstrating its potential to enhance NK cell function from AML patients. Responsiveness can be further enhanced by allogeneic NK cell addition. Anti-leukemic activity of AFM28 is confirmed in xenograft mouse models. In addition, AFM28 is well tolerated and demonstrates pharmacodynamic activity in cynomolgus monkeys. Altogether, our results indicate that AFM28 has the potential to reduce relapse-inducing residual disease and promote long-term remissions for patients with AML and MDS with a favorable safety profile.
    DOI:  https://doi.org/10.1038/s41467-025-63069-y
  20. Nat Chem Biol. 2025 Aug 22.
    α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
    Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.
      The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.
    DOI:  https://doi.org/10.1038/s41589-025-02013-z
  21. Cell Rep Med. 2025 Aug 19. pii: S2666-3791(25)00377-5. [Epub ahead of print] 102304
    Image-based drug screening combined with molecular profiling identifies signatures and drivers of therapy resistance in pediatric AML.
    Ben Haladik, Margarita Maurer-Granofszky, Peter Zoescher, Raul Jimenez-Heredia, Alexandra Frohne, Anna Segarra-Roca, Chloe Casey, Felix Kartnig, Sarah Giuliani, Christina Rashkova, Peter Repiscak, Michael N Dworzak, Giulio Superti-Furga, Kaan Boztug.
      Despite recent advances in the understanding of the genomic landscape of pediatric acute myeloid leukemia (pedAML), targeted treatments are only available for selected genomic alterations, and the functional link between genotype and outcome remains partially elusive. Functional precision medicine approaches to investigate treatment resistance and patient risk have not been applied systematically for pedAML. Here, we describe an advanced functional screening platform combining high-content imaging and deep learning-based phenotyping. In 45 patients with pedAML, we identify BCL2 and FLT3 inhibitors and standard chemotherapy as major drivers of the chemosensitivity landscape, reveal substantial differential sensitivities between risk groups, and may effectively predict individual measurable residual disease and patient risk. Integration with genomic and epigenomic data uncovers a chemotherapy-resistant primitive state vulnerable to combined BCL2 and MDM2 inhibition and HDAC inhibition. Overall, we identify early signatures of therapy resistance across genetic subgroups and prioritize targeted treatments for these functionally and epigenetically defined patient subsets.
    Keywords:  cellular differentiation; data integration; deep learning; drug screening; epigenetics; high-content imaging; pediatric AML; precision medicine
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102304
  22. Leukemia. 2025 Aug 26.
    SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.
    Jonas Thier, Sophia Hofmann, Katharina M Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P Papapetrou, Eva Hellström-Lindberg, Pedro L Moura, Vanessa Lundin.
      Myelodysplastic syndromes with somatic mutations in the splicing factor SF3B1 gene (MDS-SF3B1) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-SF3B1 remain challenging due to both the complexity of the mis-splicing landscape and its evaluation in disease-accurate models. To uncover novel RNA mis-splicing events, isogenic SF3B1K700E and SF3B1WT iPSC lines from an MDS-SF3B1 patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified SF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1), which encodes a key E1 protein at the apex of the ubiquitination cascade. UBA1 mis-splicing (UBA1ms) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34+ RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous UBA1ms in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 primary CD34+ cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.
    DOI:  https://doi.org/10.1038/s41375-025-02740-1
  23. Sci Transl Med. 2025 Aug 27. 17(813): eads9470
    Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation.
    Sachin Sharma, Vijaya Prathigudupu, Carson Cable, Lia R Serrano, Srilaxmi Nerella, Alina Chen, Ghmkin Hassan, Johnathon Lakins, Carlos Lizama Valenzuela, Tatsuya Tsukui, Roopa Ramamoorthi, Jae-Jun Kim, Holger Willenbring, Aras N Mattis, Regan F Volk, Balyn W Zaro, Joshua J Coon, Richard Beresis, William F DeGrado, Valerie M Weaver, Stephanie A Christenson, Hyunil Jo, Jennifer Y Chen.
      Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production, the possibility of promoting ECM degradation to resolve fibrosis remains largely untapped. The role of hepatic stellate cells (HSCs) in ECM degradation is an intriguing area for investigation. We previously demonstrated that inhibiting acid ceramidase (aCDase) increases ceramide in HSCs to ameliorate hepatic fibrosis. Here, we uncover a key signaling pathway that promotes ECM degradation in primary human HSCs, which is dependent upon the activation of protein kinase Cα (PKCα) and the induction of matrix metalloproteinase 1 (MMP-1) through extracellular signal-regulated kinase 1/2 (ERK1/2). Genetic reduction and pharmacological inhibition with a small molecule reduced aCDase activity, leading to increased collagen degradation and hepatic fibrosis resolution in the carbon tetrachloride (CCl4) and fructose, palmitate, cholesterol, and trans-fat (FPC) mouse models. Consistently, ceramide signaling correlated with ECM remodeling and degradation in patients with metabolic dysfunction-associated steatotic liver disease. The findings show that ceramide regulates ECM degradation and establish aCDase as a target for therapeutic regression of fibrosis.
    DOI:  https://doi.org/10.1126/scitranslmed.ads9470
  24. Discov Oncol. 2025 Aug 25. 16(1): 1612
    The instrumental role of lipids in governing the sensitivity of multiple myeloma to ferroptosis.
    Ali Habib, Oliver G Best, Charlotte E Toomes, Craig T Wallington-Gates.
      Multiple myeloma (MM) is a malignancy characterised by the uncontrolled proliferation of clonal plasma cells, primarily within the bone marrow, and is still considered incurable. A significant proportion of patients relapse with drug-refractory disease, necessitating the development of novel therapeutic approaches. Ferroptosis is a recently-characterised form of non-apoptotic programmed cell death, linked to phospholipid peroxidation, that represents a promising approach for the treatment of MM and other cancers, that are refractory to more conventional apoptosis-inducing regimens. A better understanding of the relationship between cellular lipid composition and ferroptosis sensitivity is key to harnessing this form of programmed cell death as a therapeutic approach. In addition to the cellular proportions of phospholipids containing poly- and monounsaturated fatty acids, studies to date indicate that cholesterol levels impact not only the onset and progression of haematological malignancies but also the sensitivity of a variety of different cancers to ferroptosis. Therefore, manipulating the uptake and metabolism of lipids, including glycerophospholipids and cholesterol, may be an effective means of sensitising MM cells to ferroptosis. Findings from the limited number of studies concerning ferroptosis in MM and compelling evidence from other malignancies, provide a strong rationale for further investigation of ferroptosis as a novel therapeutic approach for MM.
    Keywords:  Cancer; Cholesterol; Fatty acids; Ferroptosis; Haematology; Lipids; Multiple myeloma; Phospholipids; Saturated; Unsaturated
    DOI:  https://doi.org/10.1007/s12672-025-03444-9
  25. Science. 2025 Aug 21. 389(6762): 782-783
    A protein tunnel helps stressed lysosomes swell.
    Jennifer Lippincott-Schwartz.
      The endoplasmic reticulum donates lipids through a tunnel-like protein to help lysosomes expand.
    DOI:  https://doi.org/10.1126/science.aea5377
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