bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–11–16
nine papers selected by
William Grey, University of York
  1. Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
  2. Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence.
  3. Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.
  4. CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy.
  5. PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis.
  6. A systematic scoping review of published economic analyses of public cord blood banking: Is it time to reassess?
  7. Erythroid precursors regulate local oxygen tension and repair outcomes in the bone marrow niche.
  8. Proteomic sensors for quantitative multiplexed and spatial monitoring of kinase signaling.
  9. Protein phosphatase 2A orchestrates hematopoietic fate determination via modulation of lactate metabolism.
  1. Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]
    Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
    Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.
      Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.
    DOI:  https://doi.org/10.1182/blood.2025028933
  2. Int J Mol Sci. 2025 Oct 24. pii: 10354. [Epub ahead of print]26(21):
    Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence.
    Dongguang Li, Athena Li, Ngoc DeSouza, Shaoguang Li.
      Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow environment where both non-leukemic hematopoietic stem cells (HSCs) and LSCs reside. We believe the molecular and biological changes of these non-leukemic HSCs should be accompanied by the morphological changes of these cells. On the other hand, the quantity of these non-leukemic HSCs with morphological changes should reflect disease severity, prognosis and therapy responses. Thus, identification of non-leukemic HSCs in the leukemia bone marrow environment and monitoring of their quantity before, during and after treatments will potentially provide valuable information for correctly handling treatment plans and predicting outcomes. However, we have known that these morphological changes at the stem cell level cannot be extracted and identified by microscopic visualization with human eyes. In this study, we chose polycythemia vera (PV) as a disease model (a type of human myeloproliferative neoplasms derived from a hematopoietic stem cell harboring the JAK2V617F oncogene) to determine whether we can use artificial intelligence (AI) deep learning to identify and quantify non-leukemic HSCs obtained from bone marrow of JAK2V617F knock-in PV mice by analyzing single-cell images. We find that non-JAK2V617F-expressing HSCs are distinguishable from LSCs in the same bone marrow environment by AI with high accuracy (>96%). More importantly, we find that non-JAK2V617F-expressing HSCs from the leukemia bone marrow environment of PV mice are morphologically distinct from normal HSCs from a normal bone marrow environment of normal mice by AI with an accuracy of greater than 98%. These results help us prove the concept that non-leukemic HSCs undergo AI-recognizable morphological changes in the leukemia bone marrow environment and possess unique morphological features distinguishable from normal HSCs, providing a possibility to assess therapy responses and disease prognosis through identifying and quantitating these non-leukemic HSCs in patients.
    Keywords:  artificial intelligence; hematopoietic stem cells; leukemia stem cells; polycythemia vera
    DOI:  https://doi.org/10.3390/ijms262110354
  3. Nat Genet. 2025 Nov 11.
    Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.
    Tetsuichi Yoshizato, Christer Nilsson, Francesca Grasso, Kari Högstrand, Stefania Mazzi, Axel Winroth, Madeleine Lehander, Indira Barbosa, Gunilla Waldin, Teresa Mortera-Blanco, Monika Jansson, Mikaela Hillberg Widfeldt, Affaf Aliouat, Margs S Brennan, Ellen Markljung, Amy Hillen, Edwin Chari, Eva Hellström-Lindberg, Warren W Kretzschmar, Petter S Woll, Sten Eirik W Jacobsen.
      Dynamic steady-state lineage contribution of human hematopoietic stem cell (HSC) clones needs to be assessed over time. However, clonal contribution of HSCs has only been investigated at single time points and without assessing the critical erythroid and platelet lineages. Here we screened for somatic mutations in healthy aged individuals, identifying expanded HSC clones accessible for lineage tracing of all major blood cell lineages. In addition to HSC clones with balanced contribution to all lineages, we identified clones with all myeloid lineages but no or few B and T lymphocytes or all myeloid lineages and B cells but no T cells. No other lineage restriction patterns were reproducibly observed. Retrospective phylogenetic inferences uncovered a 'hierarchical' pattern of descendant subclones more lineage biased than their ancestral clone and a more common 'stable' pattern with descendant subclones showing highly concordant lineage contributions with their ancestral clone, despite decades of separation. Prospective lineage tracing confirmed remarkable stability over years of HSC clones with distinct lineage replenishment patterns.
    DOI:  https://doi.org/10.1038/s41588-025-02405-w
  4. Mol Ther. 2025 Nov 10. pii: S1525-0016(25)00950-5. [Epub ahead of print]
    CD33 Epitope Editing Unlocks UM171-Expanded Cord Blood Grafts for AML Immunotherapy.
    Bernhard Lehnertz, Maéva Langouët, Sophie Corneau, Tara MacRae, Maju Joe, Edward N Schmidt, Jean-Francois Spinella, Nadine Mayotte, Susan Moore, Maria Florencia Tellechea, Isabel Boivin, Loïc Papineau, Shanti Rojas-Sutterlin, Margaux Tual, Camille Jimenez Cortes, Jalila Chagraoui, Elisa Tomellini, Virginie Desse, Etienne Gagnon, Matthew S Macauley, Guy Sauvageau.
      Immunotherapies in acute myeloid leukemia (AML) are limited by shared antigen expression between leukemic and healthy hematopoietic cells, resulting in on-target toxicity. To overcome this, we developed a clinically scalable approach to engineer cord blood (CB) hematopoietic stem and progenitor cell (HSPC) grafts resistant to an established CD33-directed therapy. Combining UM171-mediated expansion with adenine base editing (ABE), we precisely disrupted the P67 epitope of CD33, centered on phenylalanine 21, which is essential for gemtuzumab ozogamicin (GO) binding. Edited variants retained CD33 expression and sialic-acid-dependent ligand binding, distinguishing this strategy from complete gene ablation. In UM171 cultures, P67 editing was efficient across multiple donors, enriched in primitive subsets, and minimally impacted expansion. In xenografts, edited grafts preserved multilineage engraftment, T-cell output, and myeloid persistence. Upon GO challenge, edited graft-derived myeloid cells were protected while CD33+ AML cells were eliminated, confirming on-tumor activity with reduced myelotoxicity. Ultra-deep exome sequencing and GUIDE-seq revealed minimal off-target activity. Together, these findings establish CD33 P67 epitope-directed base editing as a precise, scalable strategy to generate immunotherapy-compatible, UM171-expanded CB grafts that safely enable GO integration into post-transplant care.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.11.010
  5. Cancer Discov. 2025 Nov 17.
    PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis.
    Shuang Tang, Qian Zhou, Johann S Bergholz, Tao Jiang, Weihua Wang, Renlei Ji, Wendi Huang, Jiachen Wu, Yutong Li, Xiaochun Wan, Xiadi He, Qianchen Jing, Menghong Sun, Jared L Johnson, Tomer M Yaron-Barir, Da-Qiang Li, Bo Dai, Zefeng Wang, Xiaoling Li, Lewis C Cantley, Thomas M Roberts, Jean J Zhao.
      Loss of tumor suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. Here, we identify a critical druggable mechanism where PTEN-loss induces PI3Kβ phosphorylation for tumorigenesis. Using BioID interactome, we uncovered phosphorylation-dependent PI3Kβ-EPHA2 interaction in PTEN-null cells, driven by p-PI3KβY962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3KβY962. In PTEN-deficient contexts, enhanced p-PI3KβY962 forms a complex with EPHA2 and SRC, where both kinases contribute to PI3Kβ phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3KβY962 antibody detecting p-PI3KβY962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3KβY962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3KβY962 and inhibited tumor progression in PTEN-null but not PTEN-WT tumors. These findings establish p-PI3KβY962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1126
  6. Transfusion. 2025 Nov 14.
    A systematic scoping review of published economic analyses of public cord blood banking: Is it time to reassess?
    Luke E Allan, Risa Shorr, Matthew Seftel, Pierre J A Villeneuve.
       OBJECTIVES: Public banking of umbilical cord blood (UCB) remains important as a source of donor cells for hematopoietic cell transplantation (HCT). Given reductions in global cord blood transplant activity, the economic value of UCB banking may be questioned. We performed a scoping review to gain a full and current understanding of economic evaluations of public UCB banking.
    METHODS: We conducted a systematic search to June 2024 in Medline, Embase, Cochrane Central, Health Technology Assessment, Econlit, Scopus, and cumulative index to nursing and allied health literature (CINAHL) databases.
    RESULTS: Our search identified 13 studies published between 1999 and 2019, predominantly from the United States and Europe. Of these, five are classified as full economic evaluations, with two employing cost-effectiveness analysis, one applying cost-utility analysis and two applying cost-benefit analysis. Key findings reveal a shift from evaluating the optimal inventory size and costs associated with establishing cord banks, to the evaluation of strategies that increase usage and reduce costs of bank operations. Only two studies considered the societal gain from transplant survivors, noting many cord blood transplant recipients are pediatric with significant gain in quality-adjusted life years that offset the high costs of operating public cord banks. Studies addressing the needs of underrepresented populations were lacking.
    CONCLUSIONS: Our analysis highlights the evolving landscape of public UCB banking economic evaluations. Updated full economic studies are needed to understand the current landscape given potential usage by specific sub-groups of the population, reduced global usage for HCT, and the emergence of novel uses of cord blood.
    Keywords:  allogeneic; analysis; cost; economic; hematopoietic cell transplantation; public banking; umbilical cord blood; value
    DOI:  https://doi.org/10.1111/trf.18483
  7. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2522548122
    Erythroid precursors regulate local oxygen tension and repair outcomes in the bone marrow niche.
    Annemarie Lang, Joseph M Collins, Madhura P Nijsure, Simin Belali, Mohd Parvez Khan, Yasaman Moharrer, Ernestina Schipani, Yvette Y Yien, Yi Fan, Michael Gelinsky, Sergei A Vinogradov, Cameron Koch, Joel D Boerckel.
      Oxygen tension dynamically regulates stem cell fate and tissue regeneration, yet how local oxygen availability is controlled within the bone marrow niche remains poorly understood. While bone marrow injury, such as by bone fracture, disrupts marrow vasculature, the consequences for local oxygen tension remain unclear. Here, we show in mice that while the tissue oxygen tension in bone marrow is low (25 mmHg, ~4% O2), intracellular oxygenation is heterogeneous, and erythroid cells are high in oxygen. Bone fracture elevates oxygen tension in the injured bone marrow (>55 mmHg, ~8%), which persists for over a week postinjury. This oxygen elevation results not from angiogenesis, but rather from localized expansion of erythroid precursor cells in the injured bone marrow. Injury-activated erythroid precursors synthesize hemoglobin and concentrate oxygen at the injury site; however, blocking transferrin receptor 1 (CD71)-mediated iron uptake impairs hemoglobin synthesis, reduces local oxygen levels, and enhances bone regeneration through increased angiogenesis and osteogenesis. Together, these findings identify erythroid precursors as active regulators of local oxygen availability in the bone marrow niche, which may be targetable to enhance tissue regeneration.
    Keywords:  bone marrow injury; erythropoiesis; oxygen microenvironment
    DOI:  https://doi.org/10.1073/pnas.2522548122
  8. Nat Commun. 2025 Nov 13. 16(1): 9902
    Proteomic sensors for quantitative multiplexed and spatial monitoring of kinase signaling.
    William J Comstock, Marcos V A S Navarro, Deanna V Maybee, Yiseo Rho, Mateusz Wagner, Khoula Jaber, Yingzheng Wang, Marcus B Smolka.
      Understanding kinase action requires precise quantitative measurements of their activity in vivo. In addition, the ability to capture spatial information of kinase activity is crucial to deconvolute complex signaling networks, interrogate multifaceted kinase actions, and assess drug effects or genetic perturbations. Here we develop a proteomic kinase activity sensor technique (ProKAS) for the analysis of kinase signaling using mass spectrometry. ProKAS is based on a tandem array of peptide sensors with amino acid barcodes that allow multiplexed analysis for spatial, kinetic, and screening applications. We engineered a ProKAS module to simultaneously monitor the activities of the DNA damage response kinases ATR, ATM, and CHK1 in response to genotoxic drugs, while also uncovering differences between these signaling responses in the nucleus, cytosol, and replication factories. Furthermore, we developed an in silico approach for the rational design of specific substrate peptides expandable to other kinases. Overall, ProKAS is a versatile system for systematically and spatially probing kinase action in cells.
    DOI:  https://doi.org/10.1038/s41467-025-65950-2
  9. Haematologica. 2025 Nov 13.
    Protein phosphatase 2A orchestrates hematopoietic fate determination via modulation of lactate metabolism.
    Can Liu, Yao Meng, Heng Chen, Siqi Bi, Ye Tian, Zhihua Yin, Guanhua Li, Wutao Chen, Li Wu, You Wang, Nan Shen, Haibo Zhou.
      Abnormal hematopoiesis is inherently linked to metabolic reprogramming. Protein phosphatase 2A (PP2A), a master regulator of hematopoietic homeostasis, has been implicated in multiple hematological disorders. However, the precise mechanisms by which PP2A coordinates metabolic networks to govern hematopoietic fate decisions remain poorly defined. Herein, we identify lactate as a critical mediator of myeloid-biased differentiation triggered by PP2A inactivation. Genetic ablation of PPP2CA, the catalytic subunit of PP2A, results in aberrant myeloid proliferation and lymphoid depletion. Transcriptomic profiling reveals that Ppp2ca deficiency alters the expression of transcriptional regulators governing hematopoietic lineage commitment and energy metabolism. Metabolomic analyses further demonstrate enhanced lactate metabolism in Ppp2ca-deficient hematopoietic progenitors. Importantly, either haploinsufficiency or pharmacological inhibition of lactate dehydrogenase A (LDHA) in vivo effectively reverses the abnormal hematopoiesis induced by Ppp2ca deficiency. Mechanistically, Ppp2ca deletion directly promotes the transcriptional initiation of glycolytic genes (e.g., Ldha) via RNA polymerase II (Pol II). This leads to heightened lactylation of histone deacetylases (HDACs) at specific residues-lysine 412 in HDAC1 and lysine 451 in HDAC2-impairing the assembly of the HDAC1/2/SIN3A co-repressor complex on chromatin, enhancing histone acetylation, and ultimately dysregulating hematopoietic gene expression. Collectively, our work establishes the "PP2A-Lactate-HDAC lactylation" axis as a pivotal regulator of hematopoiesis and identifies LDHA as a promising therapeutic target for PP2A-associated hematological disorders.
    DOI:  https://doi.org/10.3324/haematol.2025.288868
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