bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–09–14
eighteen papers selected by
William Grey, University of York
  1. Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
  2. Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration.
  3. Red Blood Cell-Mediated Enhancement of Hematopoietic Stem Cell Functions via a Hes1-Dependent Pathway.
  4. Dissecting infant leukemia developmental origins with a hemogenic gastruloid model.
  5. CUX1 restrains latent hematopoietic stem cell plasticity by suppressing stem cell-intrinsic inflammatory pathways.
  6. Early cytokine and chemokine signals shape the anti-AML activity of bispecific engager-secreting T cells.
  7. KMT2A-rearranged leukemia: from mechanism to drug development.
  8. Nuclear respiratory factor 1 promotes cell survival in multiple myeloma under proteasome inhibition therapy.
  9. The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
  10. Induction of Moderate DNA Damage Enhances Megakaryopoiesis and Platelet Production.
  11. Development of a 29-Color Single-Tube Full Spectrum Flow Cytometry Assay for the Detection of Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia.
  12. A three-dimensional ex vivo model recapitulates in vivo features and drug resistance phenotypes in childhood acute lymphoblastic leukemia.
  13. Defined Xenofree Reprogramming of Cord Blood Progenitors to Induced Pluripotent and Blastomere-Like Stem Cells.
  14. Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours.
  15. Age-related differences in donor selection priorities for allogeneic hematopoietic transplantation.
  16. Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML.
  17. HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
  18. A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2.
  1. Blood. 2025 Sep 08. pii: blood.2024027432. [Epub ahead of print]
    Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging.
    Sen Zhang, Charles E Ayemoba, Anna M Di Staulo, Kenneth Joves, Chandani M Patel, Eva Hin Wa Leung, Maura Lima Pereira Bueno, Xiaoping Du, Mortimer Poncz, Sang-Ging Ong, Claus Nerlov, Maria Maryanovich, Constantinos Chronis, Sandra Pinho.
      Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
    DOI:  https://doi.org/10.1182/blood.2024027432
  2. Blood Adv. 2025 Sep 08. pii: bloodadvances.2024015762. [Epub ahead of print]
    Critical role of niche S100A8 for acute myeloid leukemia progression and hematopoiesis regeneration.
    Xiaoyan Liu, Jinxian Wu, Xinqi Li, Ruiyang Pan, Li Liu, Tingting Huang, Linlu Ma, Guopeng Chen, Qian Wang, Nan Zhang, Xiqin Tong, Yuxin Tan, Hongqiang Jiang, Yuxing Liang, Min Shen, Ruihang Li, Wanyue Yin, Zhang Xian, Fuling Zhou.
      The role of inflammation in the regulation of acute myeloid leukemia (AML) and stressed hematopoiesis is significant, though the molecular mechanisms are not fully understood. Here, we found that mesenchymal stromal cells (MSCs) had dysregulated expression of the inflammatory cytokine S100A8 in AML. Upregulating S100A8 in MSCs increased the proliferation of AML cells in vitro. In contrast, removing S100A8 from MSCs in the murine MLL-AF9 AML model resulted in longer survival and less infiltration of leukemia cells. S100A8 binds to the TLR4 receptor on leukemia cells, activating the PI3K/Akt pathway. In addition, removing S100A8 from MSCs caused a temporary decline in hematopoietic stem cells (HSCs) number, but facilitated long-term hematopoietic recovery under stress. Furthermore, S100A8 inhibited MSC differentiating into osteoblasts and reduced the expression of osteopontin, which is required to support HSCs. Our findings highlight the importance of niche inflammation in promoting AML development while impeding hematopoietic regeneration.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015762
  3. FASEB J. 2025 Sep 15. 39(17): e71022
    Red Blood Cell-Mediated Enhancement of Hematopoietic Stem Cell Functions via a Hes1-Dependent Pathway.
    Erika Yamashita, Soichiro Hashimoto, Hiroaki Abe, Takao Sudo, Daisuke Okuzaki, Toshiya Okawa, Masaru Ishii.
      In bone marrow, cell numbers are balanced between production and loss. After chemotherapy, blood cell counts decrease initially but later recover as hematopoietic progenitor cells expand, although the mechanisms underlying this recovery are still unclear. We investigated the influence of red blood cells (RBCs) on hematopoietic stem cell (HSC) function during bone marrow recovery. Following chemotherapy, RBC concentrations in bone marrow peaked on day 5 posttreatment, coinciding with the recovery of hematopoiesis. Coculture of HSCs with RBCs resulted in a significant increase in hematopoiesis. Direct contact between RBCs and HSCs was essential for enhancement of hematopoiesis, and HSCs precultured with RBCs resulted in greater numbers of donor-derived mature hematopoietic cells after transplantation. RNA-sequencing analysis showed that Hes1 was the most significantly upregulated transcription factor in RBC coculture, and the response to RBC-induced hematopoiesis of Hes1-deficient HSCs was reduced. These findings imply a role of RBCs and Hes1 in the enhancement of hematopoietic recovery following bone marrow stress.
    Keywords:  Hes1; bone marrow; erythrocyte; hematopoiesis; hematopoietic stem cell; red blood cell
    DOI:  https://doi.org/10.1096/fj.202500885R
  4. Elife. 2025 Sep 11. pii: RP102324. [Epub ahead of print]14
    Dissecting infant leukemia developmental origins with a hemogenic gastruloid model.
    Denise Ragusa, Chun Wai Suen, Gabriel Torregrosa Cortes, Fabio Pastorino, Ayona Johns, Ylenia Cicirò, Liza Dijkhuis, Susanne van den Brink, Michele Cilli, Connor Byrne, Giulia-Andreea Ionescu, Joana Cerveira, Kamil R Kranc, Victor Hernandez-Hernandez, Mirco Ponzoni, Anna Bigas, Jordi Garcia-Ojalvo, Alfonso Martínez Arias, Cristina Pina.
      Current in vitro models of developmental blood formation lack spatio-temporal accuracy and weakly replicate successive waves of hematopoiesis. Herein, we describe a mouse embryonic stem cell (SC)-derived 3D hemogenic gastruloid (haemGx) that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and generates hematopoietic progenitors capable of short-term engraftment of immunodeficient mice upon maturation in an in vivo niche. We took advantage of the haemGx model to interrogate the origins of infant acute myeloid leukemia (infAML). We focused on MNX1-driven leukemia, representing the commonest genetic abnormality unique to the infant group. Enforced MNX1 expression in haemGx promotes the expansion and in vitro transformation of yolk sac-like erythroid-myeloid progenitors at the HE-to-hematopoietic transition to faithfully recapitulate patient transcriptional signatures. By combining phenotypic, functional, and transcriptional profiling, including at the single-cell level, we establish the haemGx as a useful new model for the study of normal and leukemic embryonic hematopoiesis.
    Keywords:  cancer biology; development; developmental biology; gastruloid; hematopoiesis; leukemia; mouse
    DOI:  https://doi.org/10.7554/eLife.102324
  5. Blood. 2025 Sep 08. pii: blood.2024026815. [Epub ahead of print]
    CUX1 restrains latent hematopoietic stem cell plasticity by suppressing stem cell-intrinsic inflammatory pathways.
    Tanner C Martinez, Matthew R M Jotte, Saira Khan, Angela Stoddart, Hunter Z Blaylock, Ankit Malik, Megan E McNerney.
      Long-term maintenance of somatic stem cells relies on precise regulation of self-renewal and differentiation. Understanding the molecular framework for these homeostatic processes is essential for improved cellular therapies and treatment of myeloid neoplasms. CUX1 is a widely expressed, dosage-sensitive transcription factor crucial in development and frequently deleted in myeloid neoplasia in the context of -7/(del7q). Here, using novel mouse models and single-cell approaches, we report that dynamic and distinct CUX1 levels are integral to hematopoietic stem cell (HSC) activity. Knockdown of CUX1 reverses HSC differentiation and strikingly re-endows progenitors with stem cell function, accompanied by restoration of the HSC transcriptome and DNA accessibility landscape. CUX1 mediates these activities, in part, via suppressing endogenous retroelements (EREs) and the ensuing interferon-stimulated gene expression program. Both EREs and the interferon response are upregulated in CUX1-deficient acute myeloid leukemia (AML), suggesting a conserved role of CUX1 in regulating these elements. These data establish an unexpected entwinement of stem cell-intrinsic innate immune activation and the transcriptional programs of stem cell identity. Further, we reveal the profound effects of transcription factor levels in cell fate.
    DOI:  https://doi.org/10.1182/blood.2024026815
  6. Haematologica. 2025 Sep 11.
    Early cytokine and chemokine signals shape the anti-AML activity of bispecific engager-secreting T cells.
    Natalie J Holl, Adam Fearnow, Ilias Christodoulou, Stamatia C Vorri, Ruyan Rahnama, Jun Choe, Alokesh Ghosal, Weng-Ian Ng, Vinay Vyas, Hannah W Song, Ravi Varadhan, Challice L Bonifant.
      Immunotherapies, including cell therapies, are effective anti-cancer agents. However, cellular product persistence can be limiting with short functional duration of activity contributing to disease relapse. A variety of manufacturing protocols are used to generate therapeutic engineered T-cells; these differ in techniques used for T-cell isolation, activation, genetic modification, and other methodology. We sought to determine how preselection affected the phenotype of T cells engineered to secrete a CD123xCD3 bispecific engager (ENG-T). These cells were designed to treat acute myeloid leukemia (AML). We evaluated the effect of T-cell selection on transduction efficiency, T-cell activation, short- and long-term anti-AML cytotoxicity, and gene transcription. Unselected, CD4, CD8, and CD4/CD8 pre-selected ENG-T cells have minor differences in T-cell subset components, equivalent activation, and equal cytotoxicity in short-term assays. While unselected and CD4/CD8-selected ENG-T cells have identical CD4:CD8 composition prior to target cell exposure, serial stimulation in vitro showed CD4/CD8 pre-selection supports ENG-T cell survival and long-term activity. Likewise, CD4 and CD4/CD8 pre-selected ENG-T cells display superior anti-tumor efficacy and prolong murine survival in AML xenografts. Unselected ENG-T cells are exposed to cytokines during early manufacture that imprint upregulation of intracellular inflammatory pathways. This early activation likely underpins long-term observed functional differences. Pre-selection of T cells from banked patient biospecimens decreased blast contamination, exposure to inflammatory cytokines, and may improve T-cell expansion during manufacture. Pre-selection of T-cell products should continue to be performed to enhance the quality of clinical cellular therapeutics.
    DOI:  https://doi.org/10.3324/haematol.2025.287934
  7. Exp Hematol. 2025 Sep 06. pii: S0301-472X(25)00536-3. [Epub ahead of print] 105247
    KMT2A-rearranged leukemia: from mechanism to drug development.
    Patricia Ernst, Perpetual Kyei, Akihiko Yokoyama.
      Gene rearrangements of the human MLL gene (also known as KMT2A) generate multiple fusion oncoproteins which cause leukemia with poor prognosis. MLL is an epigenetic regulator that reads and writes epigenetic information and has an evolutionarily conserved role maintaining expression of Homeotic (HOX) genes during embryonic development. Most MLL gene rearrangements found in leukemia generate a constitutively active version of the wild-type protein, which causes overexpression of HOX and other genes and leukemic transformation of normal hematopoietic progenitors. Elucidating the molecular mechanisms underlying how MLL activates gene expression and how gene rearrangements affect this gene-regulating activity provided therapeutic opportunities to block fusion oncoprotein-specific activities. One uniform molecular dependency of MLL fusion oncoproteins is its interaction with the chromatin-binding partner MENIN that is essential to maintain leukemic transformation. MENIN inhibitors that interfere with the MLL-MENIN interaction have been developed and are now entering clinical practice. Also, the MLL complex physically interacts with several histone acetyl transferases (HATs), including MOZ/MORF, HBO1, and EP300/CREBBP to effect MLL-MENIN-dependent gene activation. Aberrant recruitment of these HATs and other transcriptional effector complexes are key differences between MLL and MLL fusion oncoproteins. In this review, we first summarize our current understanding of wild-type MLL function and aberrant function of its oncogenic variants. We then discuss in detail how chromosomal translocations generate constitutive active forms of MLL and categorize them into five major classes. We touch on the collaborative gene activation by MLL and specific interacting HATs. Lastly, we discuss how these mechanistic insights have led to the development of the first-in-class MENIN inhibitors and discuss efforts to anticipate and treat both genetic and non-genetic mechanisms of resistance. Teaser abstract: MLL fusion oncoproteins often transform cells in particular developmental states without the need for additional mutations. Insights gained studying how this occurs has yielded a wealth of mechanistic and biological insights. Here we review some of the detailed molecular mechanisms leading to leukemia development as well as how understanding these mechanisms resulted in the development of targeted therapies, and ongoing efforts to anticipate and prevent resistance to targeted therapies.
    Keywords:  KMT2A; Leukemia; MENIN; MLL; protein-interaction inhibitors
    DOI:  https://doi.org/10.1016/j.exphem.2025.105247
  8. Blood. 2025 Sep 08. pii: blood.2025028441. [Epub ahead of print]
    Nuclear respiratory factor 1 promotes cell survival in multiple myeloma under proteasome inhibition therapy.
    Tiziana Bruno, Maria Chiara Cappelletto, Clelia Cortile, Stefano Di Giovenale, Bruno Amadio, Francesca De Nicola, Italia Falcone, Stefano Giuliani, Belinda Palermo, Valeria Catena, Ludovica Ciuffreda, Fulvia Cerruti, Paolo Cascio, Roberta Merola, Serena Masi, Valentina De Pascale, Ombretta Annibali, Silvia Ferraro, Svitlana Gumenyuk, Francesco Pisani, Francesco Marchesi, Andrea Mengarelli, Maurizio Fanciulli, Giacomo Corleone.
      Multiple myeloma (MM) continues to be an incurable malignancy, even with recent therapeutic advancements. While epigenetic dysregulation at cis-regulatory elements is known to drive disease progression, the complete molecular mechanisms underlying these alterations are poorly understood. Using ATAC-seq analysis combined with computational footprinting of CD138+ cells from 55 MM patients, we depicted the dynamic changes in chromatin accessibility during disease progression and identified Nuclear Respiratory Factor 1 (NRF1) as a master regulator of vital MM survival pathways. We demonstrated that NRF1 maintains proteasome homeostasis by orchestrating the ubiquitination pathway, which is essential for MM cell survival. We discovered a novel enhancer element that physically interacts with the NRF1 promoter, sustaining its expression. Targeting this enhancer RNA reduced NRF1 levels and increased tumor cell sensitivity to bortezomib (BTZ), suggesting therapeutic potential. In xenograft models, we showed that antisense oligonucleotides (ASOs) targeting the NRF1 enhancer, either alone or combined with BTZ, significantly decreased tumor burden and improved survival. Our findings reveal a previously unknown NRF1-dependent mechanism regulating MM cell survival and present a promising therapeutic approach through manipulation of its regulatory network.
    DOI:  https://doi.org/10.1182/blood.2025028441
  9. Blood Adv. 2025 Sep 08. pii: bloodadvances.2024015427. [Epub ahead of print]
    The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
    Kaifee Arman, Julie Ross, Eva-Maria Piskor, Luca Lazzari, Virginie Calderon, Gaspard Reulet, Maria Vera, Edlie St Hilaire, Hugo Wurtele, Brian T Wilhelm, Tarik Möröy.
      Acute myeloid leukemia (AML) with rearrangement of the mixed lineage leukemia gene express MLL-AF9 fusion protein, a transcription factor that impairs differentiation and drives expansion of leukemic cells. We report here that the zinc finger protein GFI1 together with the histone methyltransferase LSD1 occupies the promoter and regulates expression of the lncRNA ELDR in the MLL-r AML cell line THP-1. Forced ELDR overexpression enhanced the growth inhibition of an LSD1i/ATRA combination treatment and reduced the capacity of these cells to generate leukemia in xenografts, leading to a longer leukemia-free survival. We found that ELDR binds the clamp protein PCNA and the MCM5 helicases causing defects of DNA replication fork progression. Moreover, AML cells overexpressing ELDR showed reduced chromatin accessibility and transcription at α-satellite repeats in centromeres. In addition, ELDR RNA was detected close to MLL-AF9 at centromeres suggesting that it impedes leukemic progression preferentially of MLL-r AML by interfering with both DNA replication and centromeric transcription. Our findings reveal novel functions of the lncRNA ELDR in DNA replication and centromere biology when expressed at high levels in AML cells with MLL rearrangements. These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be utilized as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015427
  10. Blood Adv. 2025 Sep 12. pii: bloodadvances.2025017375. [Epub ahead of print]
    Induction of Moderate DNA Damage Enhances Megakaryopoiesis and Platelet Production.
    Virginia Camacho, Roelof Bekendam, Andrew P Stone, Maria N Barrachina, Siobhan Branfield, Estelle Carminita, Isabelle C Becker, Dong H Lee, Ethan Walsey, Clementine Payne, Jakub Piotr Kaplan, Julia Tilburg, Sharmistha Pal, Luis Francisco Zirnberger Batista, Joseph E Italiano, Kellie R Machlus.
      Megakaryocytes (MKs) are large, hematopoietic cells with a polyploid, multi-lobulated nucleus. While DNA replication in MKs (endomitosis) is well studied, limited investigations have examined the impact of DNA instability on megakaryopoiesis. Poly-ADP ribose polymerase (PARP) inhibitors are chemotherapeutics that result in accumulation of DNA damage and are commonly associated with thrombocytopenia, presumably mediated through platelet progenitors, MKs. To explore PARP inhibitor-induced thrombocytopenia, we treated mice with the PARP inhibitor Niraparib. While high dose Niraparib treatment led to thrombocytopenia, consistent with clinical observations, lower dosage treatment led to a significant increase in bone marrow MKs, MK progenitors, and circulating platelets. This increase was accompanied by elevated DNA damage in both MKs and MK progenitors, as measured by gH2AX accumulation and comet assays. Notably, platelets from Niraparib-treated mice were functionally normal in their response to ADP, TRAP, and collagen. Treatment of mice with low-dose gamma-irradiation similarly led to DNA damage in MKs and resulted in increased MK and platelet counts, suggesting that moderate DNA damage is a common mechanism that enhances megakaryopoiesis and platelet counts. These data reveal a previously unknown relationship between MKs and DNA damage and present a novel target for triggering enhanced platelet production in vivo.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017375
  11. Cytometry A. 2025 Sep 12.
    Development of a 29-Color Single-Tube Full Spectrum Flow Cytometry Assay for the Detection of Measurable Residual Disease and Leukemic Stem Cells in Acute Myeloid Leukemia.
    Zhong Zhang, Miriam Wilhelm, Ines Sieber, Hartmut Döhner, Michaela Feuring.
      Multiparametric flow cytometry (MFC) is widely used to detect measurable residual disease (MRD) in acute myeloid leukemia (AML). However, conventional flow assays require multiple tubes, with an additional tube for leukemia stem cell (LSC) analysis and lack hemodilution evaluation. Spectral flow cytometry (SFC) can overcome the limitation of flow channels and has the potential for multifunctional design using a single tube. We developed a 29-color single-tube assay that adheres to the recommendations of the European Leukemia Network Flow-MRD Working Party and incorporates the simultaneous evaluation of MRD, LSC, and hemodilution. The Complexity Index of the assay was calculated at 9.08. Through limit dilution experiments using the KG-1α AML cell line, we determined the limit of blank (LOB), limit of detection (LOD), and limit of quantification (LOQ) for four leukemia-associated immunophenotypes (LAIP). The assay easily achieved the minimum sensitivity requirement for MRD detection ≤ 0.1% with minimal intra- and interassay variations. Background signals for 24 LAIPs and 10 LSC immunophenotypes were evaluated in eight healthy bone marrow (BM) samples. The single-tube SFC assay was compared with the five-tube conventional assay by analyzing 20 AML BM samples, demonstrating high concordance. To assess hemodilution, markers to detect established parameters, including immature granulocytes, neutrophils, mast cells, and plasma cells, were included. In summary, we provide a versatile single-tube 29-color SFC-based MRD assay that minimizes cell requirements, integrates LSC evaluation, and assesses hemodilution. This assay has the potential to improve the reliability and simplicity of MRD detection.
    Keywords:  acute myeloid leukemia; full spectrum flow cytometry; leukemia stem cell; measurable residual disease
    DOI:  https://doi.org/10.1002/cyto.a.24958
  12. Leukemia. 2025 Sep 10.
    A three-dimensional ex vivo model recapitulates in vivo features and drug resistance phenotypes in childhood acute lymphoblastic leukemia.
    Magdalini Kanari, Iria Jimenez Garcia, Fabio D Steffen, Lisa A Krattiger, Charles Bataclan, Wangjie Liu, Benjamin R Simona, Bart Deplancke, Olaia Naveiras, Martin Ehrbar, Beat Bornhauser, Jean-Pierre Bourquin.
      Acute lymphoblastic leukemia (ALL) preferentially localizes in the bone marrow (BM) and displays recurrent patterns of medullary and extra-medullary involvement. Leukemic cells exploit their niche for propagation and survive selective pressure by chemotherapy in the BM microenvironment, suggesting the existence of protective mechanisms. Here, we established a three-dimensional (3D) BM mimic with human mesenchymal stromal cells and endothelial cells that resemble vasculature-like structures to explore the interdependence of leukemic cells with their microenvironment. This model recapitulates recurrent topologic differences between B-cell and T-cell precursor ALL, whereby B-ALL interacts more closely with the mesenchymal compartment. Migration versatility was found to be associated with subtype, consistent with increased motility observed in T-ALL in vivo. Single-cell RNA signatures revealed similarities to profiles from in vivo patient derived xenografts, suggesting relevant states ex vivo. Furthermore, enhanced migration, adherence and cell cycle heterogeneity was visualized in our co-culture model. Finally, drug response experiments in this 3D model confirm clinically relevant sensitivity and resistance patterns that reflect specific disease phenotypes and may provide a broader dynamic range for drug response testing.
    DOI:  https://doi.org/10.1038/s41375-025-02739-8
  13. J Vis Exp. 2025 Aug 22.
    Defined Xenofree Reprogramming of Cord Blood Progenitors to Induced Pluripotent and Blastomere-Like Stem Cells.
    Tea Soon Park, Ludovic Zimmerlin, Elias T Zambidis.
      Human cord blood (CB) myeloid progenitor reprogramming to a high-fidelity human induced pluripotent stem cell (hiPSC) state can be achieved using non-integrating episomal vectors and stromal signals. These conventional, primed CB-hiPSC lines can subsequently be chemically reverted with high efficiencies to a blastomere-like Tankyrase/PARP Inhibitor-Regulated Naive Stem Cell (TIRN-SC) state with functional totipotency. PARP-regulated TIRN-SCs are human stem cells with high epigenetic plasticity, stable epigenomic imprints, and have greater differentiation potency than conventional, lineage-primed hiPSCs. Here, optimized XF/FF methods are outlined for efficient mesenchymal stroma-activated episomal reprogramming of CD34+ CD33+ CB myeloid progenitors into conventional XF/FF hiPSC. TIRN reversion reproducibly potentiated XF/FF conventional hiPSC to adopt transcriptional, epigenetic, and functional features of cleavage-stage human embryo cells with decreased lineage-primed gene expression. We validated that TIRN-reverted CB-derived XF-hiPSC displayed marked improvement in directed multi-lineage differentiation (including hematovascular lineages) across a broad repertoire of genetically independent backgrounds. These methods serve as a first step for generating cGMP-compliant TIRN-SC lines for clinical-grade HLA-defined 'Universal' donor TIRN-SC (UTIRN-SC) banks. The derivation of UTIRN-SC lines with improved differentiation versatility from CD34+ CD33+ CB progenitors could have a high impact on regenerative medicine. For example, UTIRN-SCs could generate tissue banks of HLA-defined, cryo-preserved cardiac, vascular, and neural donor progenitors for comprehensive multi-lineage "off-the-shelf" cellular therapies.
    DOI:  https://doi.org/10.3791/68613
  14. Nature. 2025 Sep 10.
    Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours.
    Samarth Hegde, Bruno Giotti, Brian Y Soong, Laszlo Halasz, Jessica Le Berichel, Maximilian M Schaefer, Benoit Kloeckner, Raphaël Mattiuz, Matthew D Park, Assaf Magen, Adam Marks, Meriem Belabed, Pauline Hamon, Theodore Chin, Leanna Troncoso, Juliana J Lee, Kaili Fan, Dughan Ahimovic, Michael J Bale, Kai Nie, Grace Chung, Darwin D'souza, Krista Angeliadis, Seunghee Kim-Schulze, Raja M Flores, Andrew J Kaufman, Florent Ginhoux, Jason D Buenrostro, Steven Z Josefowicz, Alexander M Tsankov, Thomas U Marron, Sai Ma, Brian D Brown, Miriam Merad.
      Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME)1 and tumour-enhanced myelopoiesis in the bone marrow fuels these populations2. Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09493-y
  15. Haematologica. 2025 Sep 11.
    Age-related differences in donor selection priorities for allogeneic hematopoietic transplantation.
    Koji Kawamura, Junya Kanda, Sachiko Seo, Fumihiko Kimura, Masahiro Hirayama, Naoyuki Uchida, Noriko Doki, Wataru Takeda, Tetsuya Nishida, Yuta Katayama, Masatsugu Tanaka, Masashi Sawa, Satoshi Yoshihara, Tetsuya Eto, Toshiro Kawakita, Hirohisa Nakamae, Shuichi Ota, Fumihiko Ishimaru, Takahiro Fukuda, Yoshiko Atsuta, Yoshinobu Kanda.
      Patient age might influence donor selection priorities in allogeneic hematopoietic stem cell transplantation (allo-HCT), due to the differences in donor age, organ function, and resistance to graft-versus-host disease between younger and older patients. We compared the transplant outcomes among human leukocyte antigen (HLA)-matched related donors (M-RDs, n=4,106), HLA 1-antigen-mismatched related donors (1MM-RDs, n=592), HLA 2-3-antigen-mismatched related donors (23MM-RDs, n=882), HLA-matched unrelated donors (M-UDs, n=3,927), HLA 1-locus-mismatched unrelated donors (1MM-UDs, n=2,474), and unrelated cord blood units (U-CBs, n=5,867) between patients aged.
    DOI:  https://doi.org/10.3324/haematol.2025.288004
  16. Leukemia. 2025 Sep 10.
    Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML.
    Denis Ohlstrom, Mojtaba Bakhtiari, Hope Mumme, Marina Michaud, Alejandro De Janon Gutierrez, Deborah DeRyckere, Katherine E Ferguson, Frank Chien, William Pilcher, Sarthak Satpathy, Sean Jordan, Douglas Graham, Swati Bhasin, Manoj Bhasin.
      Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While identification of cytogenetic lesions improved risk stratification, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. To deeply characterize pAML heterogeneity and identify poor outcome-associated blast cell profiles, we performed an analysis on 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. The longitudinal analysis on cell abundances at the time of disease diagnosis, end of induction, and relapse identified treatment resistant stem-like blast cells specific to RUNX1::RUNX1T1, FLT3-ITD, and CBFB::MYH11 patients that are associated with poor outcomes. Treatment resistant blast cells from RUNX1::RUNX1T1 were found to associate with T cell exhaustion, while those from FLT-ITD utilized enriched antioxidant metabolism to persist through treatment. Interestingly, the analysis also identified novel mast cell-like pAML associated with treatment resistance and poor outcomes. Deconvolution of ex vivo treatment data and subsequent in vitro validation identified bortezomib (RUNX1), ponatinib, and venetoclax (FLT3) as specifically potent against treatment resistant blasts from the respective cytogenetic groups. Our findings indicate immature and mature pAML subtypes are promising biomarkers for enhanced patient risk stratification and identifies targeted agents to increase their clearance after treatment.
    DOI:  https://doi.org/10.1038/s41375-025-02748-7
  17. Cell. 2025 Sep 02. pii: S0092-8674(25)00929-8. [Epub ahead of print]
    HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
    Jeany Delafiori, Mohammed Shahraz, Andreas Eisenbarth, Volker Hilsenstein, Bernhard Drotleff, Alberto Bailoni, Bishoy Wadie, Måns Ekelöf, Alexander Mattausch, Theodore Alexandrov.
      Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses. Profiling HeLa and NIH3T3 cells, we detected 73 small-molecule metabolites validated by bulk liquid chromatography tandem MS (LC-MS/MS), achieving high reproducibility and single-cell resolution. Interrogating nine NCI-60 cancer cell lines and HeLa, we identified cell-type markers in subpopulations and metabolic hubs. Upon inhibiting glycolysis in HeLa cells, we observed emerging glucose-centered metabolic coordination and intra-condition heterogeneity. Overall, we demonstrate how HT SpaceM enables robust, large-scale SCM across over 140,000 cells from 132 samples and provide guidance on how to interpret metabolic insights beyond population averages.
    Keywords:  LC-MS/MS; MALDI-imaging mass spectrometry; NCI-60; SpaceM; co-abundance; heterogeneity; high-throughput; reproducibility; single-cell metabolomics; small-molecule metabolites
    DOI:  https://doi.org/10.1016/j.cell.2025.08.015
  18. Nat Biotechnol. 2025 Sep 10.
    A rapid imaging-based screen for induced-proximity degraders identifies a potent degrader of oncoprotein SKP2.
    Yankai Chu, Shishuang Chen, Mingyang Yang, Yin Chen, Huiling Fang, Pinyu Huang, Yueru Xie, Chi Sun, Yun Chen, Baoding Zhang, Li Li, Hongchen Mu, Ding Song, Wentao Cheng, Chao Wang, Wei Jiang, Xiaolan Xu, Zhengjin He, Shuo Chen, Mingxian Liu, Jingchuan Ma, Man Yang, Jiaqi Cao, Jing Gao, Jiali Shen, Lulu Zhang, Yu Bai, Zheyi Liu, Jingyao Chen, Siqi Dai, Yi Arial Zeng, Yun Zhao, Hu Zhou, Chong Chen, Huanwei Ru, Li Tan, Ximin Chi, Fangjun Wang, Daming Gao, Moubin Lin, Xianming Deng, Hai Jiang.
      Targeted protein degraders hold potential as therapeutic agents to target conventionally 'undruggable' proteins. Here, we develop a high-throughput screen, DEath FUSion Escaper (DEFUSE), to identify small-molecule protein degraders. By conjugating the protein of interest to a fast-acting triggerable death protein, this approach translates target protein degradation into a cell survival phenotype to illustrate the presence of degraders. Using this method, we discovered a small molecule (SKPer1) that triggers degradation of the oncoprotein SKP2 and specifically kills SKP2-expressing cancer cells. Mechanistically, SKPer1 acts as an induced-proximity degrader by inducing interaction between SKP2 and an E3 ligase, STUB1, resulting in SKP2 ubiquitination and degradation. SKPer1 exhibits substantial tumour suppression with good safety profiles in vivo. We further show that a sequence of ten amino acids from SKP2 can serve as a versatile degradation tag.
    DOI:  https://doi.org/10.1038/s41587-025-02793-8
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