bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–11–30
twenty-two papers selected by
William Grey, University of York
  1. Mitofusin agonists enhances long-term engraftment and potency of HSC cultures in vivo.
  2. Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells.
  3. Depletion of microenvironmental syndecan-2 impairs hematopoietic stem cell self-renewal and cytokine responses.
  4. Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1.
  5. Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells.
  6. Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury.
  7. Inhibition of farnesyltransferase activity diminishes hematopoietic stem cell ex vivo expansion ability.
  8. Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML.
  9. Early persistence of recipient stem-cells and T-cell dysregulation are associated with relapse after transplant in AML/MDS.
  10. Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells.
  11. PRDM15 regulates differentiation and proliferation of hematopoietic stem cells.
  12. Multipotent progenitors with distinct origins, clonal lineage fates, transcriptomes, and surface markers yield two hematopoietic trees.
  13. The AML cellular state space unveils NPM1 immune evasion subtypes with distinct clinical outcomes.
  14. Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.
  15. Space-associated stem cell hallmarks of aging and resilience in astronauts.
  16. Inhibitors supercharge kinase turnover through native proteolytic circuits.
  17. Harnessing the E3 ligase SPOP for targeted degradation of the NUP98::KDM5A fusion oncoprotein.
  18. TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
  19. Development of a CRISPR/Cas9-degron system that enables in vivo specific gene depletion in leukemia models.
  20. Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.
  21. NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms.
  22. A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity.
  1. bioRxiv. 2025 Oct 27. pii: 2025.10.27.684807. [Epub ahead of print]
    Mitofusin agonists enhances long-term engraftment and potency of HSC cultures in vivo.
    Alyssa Biondo, Gabriela Candelaria, Daniel Jin, Emily Lin, Daniel McLaughlin, Zhaolun Liang, Katherine Leong, Christopher D Hillyer, Hans-Willem Snoeck, Larry L Luchsinger.
      Umbilical cord blood (CBU) is a valuable source of hematopoietic stem cells (HSCs) due to its superior donor compatibility and lower incidence of graft-versus-host disease. However, its limited HSC content restricts its use in adult transplantation, necessitating new targets for ex vivo expansion and improved HSC potency. Mitofusin 2 (MFN2), a mitochondrial membrane fusion protein, is necessary for preserving HSC function and agonists of mitofusin activity have been characterized. We report that ex vivo culture of CBU HSCs with mitofusin agonists (MAs) enhances long-term repopulating activity by over five-fold in both primary and secondary transplantation assays without changes of total nucleated cells or phenotypic HSCs. Mechanistically, MA-treated HSCs show suppressed protein synthesis, increased autophagic flux, and elevated lysosomal acidification. Transcriptomic analysis implicates downregulation of MTOR signaling, and immunoprecipitation studies confirm a direct interaction between MFN2 and MTOR. These data support a model in which fusion-competent MFN2 sequesters MTOR, promoting a catabolic state that preserves HSC potency. Our findings suggest a novel MFN2-MTOR regulatory axis that enhances the functional expansion of human HSCs for potential therapeutic application.
    DOI:  https://doi.org/10.1101/2025.10.27.684807
  2. Cell Stem Cell. 2025 Nov 24. pii: S1934-5909(25)00405-9. [Epub ahead of print]
    Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells.
    Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G Beaumont, Deanna L Benson, Nikolaos Tzavaras, Mickaël M Ménager, Saghi Ghaffari.
      Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging-beyond their passive mediation of autophagy-is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
    Keywords:  MMP; aging; cGas-STING; hematopoietic stem cell; inflammation; interferon; lysosomes; mitochondria; mtDNA; quiescence
    DOI:  https://doi.org/10.1016/j.stem.2025.10.012
  3. bioRxiv. 2025 Nov 09. pii: 2025.11.07.687077. [Epub ahead of print]
    Depletion of microenvironmental syndecan-2 impairs hematopoietic stem cell self-renewal and cytokine responses.
    Matthew W Hagen, Nicollette J Setiawan, Rachel Wellington, Kelsey A Woodruff, Carli Newman, Taylor M Billings, Mary N Nazzaro, Brandon Hadland, Christina M Termini.
      Syndecan-2 is a heparan sulfate proteoglycan highly enriched on murine bone marrow hematopoietic stem cells (HSCs) compared to terminally differentiated hematopoietic cells. Syndecan-2 binds growth factors via its heparan sulfate glycosaminoglycan chains to coordinate cell signaling. Knockdown of syndecan-2 reduces HSC self-renewal ability and promotes cell cycling via Cdkn1c . In this study, we analyzed the function of syndecan-2 expressed by bone marrow niche cells in hematopoiesis and HSC self-renewal. We determined that syndecan-2 is highly expressed by bone marrow mesenchymal stromal cells and moderately expressed by endothelial cells. To test the function of niche-expressed syndecan-2 in hematopoiesis, we generated transgenic mice depleted of Sdc2 in Lepr- targeted mesenchymal stromal cells ( Sdc2 ΔMSC mice) or Cdh5 -targeted endothelial cells ( Sdc2 ΔEC mice). Loss of syndecan-2 from endothelial or mesenchymal stromal cells did not change bone marrow HSC frequencies or numbers. However, depletion of syndecan-2 from Lepr -targeted mesenchymal stromal cells, but not Cdh5 -targeted endothelial cells, diminishes HSC self-renewal ability analyzed by competitive transplants into lethally irradiated mice. Ex vivo studies further show that HSCs co-cultured with HS-5 stromal cells depleted of SDC2 exhaust more rapidly than HSCs cultured with control HS-5 cells. Single-cell RNA sequencing analyses reveal that the depletion of Sdc2 from mesenchymal stromal cells significantly remodels the HSC transcriptome by enriching for pathways associated with excessive growth factor signaling. Together, our findings suggest that HSC self-renewal is supported by cell-extrinsic mechanisms enacted by syndecan-2 from the MSC niche, highlighting the importance of the niche proteoglycome in HSC functions.
    KEY POINTS: The heparan sulfate proteoglycan syndecan-2 expressed by mesenchymal stromal cells but not endothelial cells regulates HSC self-renewal Depletion of syndecan-2 from Lepr -targeted mesenchymal stromal cells remodels the hematopoietic stem cell transcriptional landscape.
    DOI:  https://doi.org/10.1101/2025.11.07.687077
  4. J Clin Invest. 2025 Nov 25. pii: e181943. [Epub ahead of print]
    Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1.
    Hayle Kincross, Ya-Chi Angela Mo, Xuan Wang, Linda Chang, Gerben Duns, Franziska Mey, Jihong Jiang, Zurui Zhu, Naomi Isak, Harwood Kwan, Tammy Ty Lau, T Roderick Docking, Pranav Garg, Jessica Tran, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Nadia Gharaee, Elijah Willie, Jeremy Dk Parker, Joshua Bridgers, Davis Wood, Ramon I Klein Geltink, Gregg B Morin, Aly Karsan.
      Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequencing data from 1,727 unique individual AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples with mutual exclusivity. The SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex gene, FBXO11, was the most significantly downregulated gene of the SCF complex in AML. We found that FBXO11 interacts with and catalyzes K63-linked ubiquitination of LONP1 in the cytosol, to promote LONP1 entry into mitochondria. We show that depletion of FBXO11 or LONP1 reduces mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV. Reduced mitochondrial respiration secondary to FBXO11 or LONP1 depletion imparted myeloid-biased stem cell properties in primary CD34+ hematopoietic stem and progenitor cells (HSPC) in vitro. In a human xenograft model, depletion of FBXO11 cooperated with AML1-ETO and mutant KRASG12D to generate serially transplantable AML. Our findings suggest that reduced FBXO11 cooperates to initiate AML by priming HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.
    Keywords:  Hematology; Hematopoietic stem cells; Leukemias; Mitochondria; Stem cells
    DOI:  https://doi.org/10.1172/JCI181943
  5. Nat Aging. 2025 Nov 24.
    Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells.
    Eva Mejía-Ramírez, Pablo Iáñez Picazo, Barbara Walter, Sara Montserrat-Vazquez, Francesco Affuso, Stefan Wieser, Fabio Pezzano, Loïc Reymond, Jorge Castillo-Robles, Francesca Matteini, Loris Mularoni, Dídac Maciá, Ángel Raya, Verena Ruprecht, Yi Zheng, Paula Petrone, M Carolina Florian.
      Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.
    DOI:  https://doi.org/10.1038/s43587-025-01014-w
  6. bioRxiv. 2025 Oct 06. pii: 2025.10.05.680535. [Epub ahead of print]
    Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury.
    Kyleigh A Rodgers, Elizabeth A R Garfinkle, Kristina A Kigerl, Elham Asghari Adib, Katherine A Mifflin, Jodie Hall, Rohan Kulkarni, Cankun Wang, Chinmayee Goda, Ana C Rodrigues Dias, Zhen Guan, Malith Karunasiri, Qin Ma, Katherine E Miller, Adrienne M Dorrance, Phillip G Popovich.
      Spinal cord injury (SCI) exerts profound systemic effects that extend beyond the nervous system, including the onset of bone marrow failure. Here, we show that SCI impairs the ability of hematopoietic stem cells (HSCs) to exit quiescence, proliferate, and differentiate, ultimately compromising long-term hematopoiesis. Using in-vivo transplantation assays, single-cell transcriptomics, and chromatin accessibility profiling, we show that SCI suppresses canonical stress-induced transcriptional programs in HSCs, including those governing cell cycle progression and DNA repair. These transcriptional changes are accompanied by epigenetic remodeling, with reduced chromatin accessibility at key genomic loci required for genome maintenance. Functionally, SCI HSCs exhibit impaired proliferation, persistent DNA damage, and an inability to resolve oxidative stress, even in the absence of ongoing injury. These defects culminate in bone marrow failure and pancytopenia in recipient mice. Our findings reveal a previously unrecognized systemic consequence of SCI and underscore the need for therapeutic strategies to preserve hematopoietic integrity following SCI.
    Key Findings: SCI prevents stress-induced transcriptional programs in HSCs.DNA repair genes in HSPCs are epigenetically silenced after SCI.SCI HSCs accumulate ROS and DNA damage.SCI HSCs are hypersensitive to genotoxic stress.SCI HSCs fail long-term hematopoiesis post-transplant.
    DOI:  https://doi.org/10.1101/2025.10.05.680535
  7. bioRxiv. 2025 Oct 31. pii: 2025.10.30.685582. [Epub ahead of print]
    Inhibition of farnesyltransferase activity diminishes hematopoietic stem cell ex vivo expansion ability.
    Carli Newman, Isabella M Alves, Matthew W Hagen, Rachel Wellington, Brandon Hadland, Anita M Quintana, Christina Marie Termini.
      The rationale underlying this work is that elucidating the contribution of farnesyltransferase activity to hematopoietic stem cell expansion ex vivo will provide knowledge needed to better support hematopoietic stem cell expansion techniques for clinical applications that rely on this approach, like hematopoietic cell transplants and gene therapy. We discovered that pharmacological inhibition of farnesyltransferase activity with lonafarnib substantially diminished the ex vivo expansion potential of human and mouse hematopoietic stem cells, highlighting that hematopoietic stem cells rely on isoprenoids for their ex vivo maintenance.
    DOI:  https://doi.org/10.1101/2025.10.30.685582
  8. bioRxiv. 2025 Oct 15. pii: 2025.10.13.681683. [Epub ahead of print]
    Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML.
    Mina M Tayari, Helena Gomes Dos Santos, Felipe Beckedorff, Tulasigeri Totiger, Adnan Mookhtiar, Anna Lesley Kingham, Guilherme Miura Lavezzo, Gloria Mas Martin, Hsuan-Ting Huang, Efe Karaca, Daniel Bilbao, Justin Taylor, Ramin Shiekhattar, Justin M Watts.
      Acute myeloid leukemia (AML) harboring MLL ( MLL1, KMT2A ) rearrangement ( MLL-r ) remains a lethal subtype with limited durable responses to single-agent menin inhibition. To define rational combination strategies, we performed a high-throughput screen of >900 epigenetic modulators in combination with menin inhibition in MLL-r AML models. This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat. Mechanistically, LSD1 was found to interact with LEDGF/p75 (PSIP1), a chromatin-anchoring cofactor of the menin-MLL complex at H3K36me3 marked euchromatin. Chromatin profiling revealed extensive co-occupancy of LSD1 and menin-MLL components at leukemogenic loci in MLL-r AML cells. Dual inhibition of menin and LSD1 dismantled this chromatin complex, evicted H3K36me3 from LEDGF-bound sites, and reprogrammed transcription toward myeloid differentiation. Combined menin and LSD1 blockade repressed canonical MLL targets, including HOXA9, MYC, FLT3, PBX3 , and CDK6 , while restoring H3K36me3 and H3K4me3 and activating differentiation-associated genes. In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.
    DOI:  https://doi.org/10.1101/2025.10.13.681683
  9. bioRxiv. 2025 Nov 14. pii: 2025.11.13.688350. [Epub ahead of print]
    Early persistence of recipient stem-cells and T-cell dysregulation are associated with relapse after transplant in AML/MDS.
    Nurefsan E Sariipek, Ksenia R Safina, Wesley S Lu, Shuqiang Li, J Thomas Janes, McKayla Van Orden, Kenneth J Livak, Haynes Heaton, Vincent T Ho, John Koreth, Marlise R Luskin, Gabriel K Griffin, Jacqueline S Garcia, R Coleman Lindsley, Corey Cutler, Robert J Soiffer, Jerome Ritz, Catherine J Wu, Joseph H Antin, Andrew A Lane, Mahasweta Gooptu, Peter van Galen.
      Hematopoietic stem cell transplantation (HSCT) offers the best curative option for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), yet relapse remains common. Current relapse detection methods are often too late for effective intervention. To identify earlier predictors and therapeutic targets, we performed longitudinal single-cell RNA and T cell receptor (TCR) sequencing of bone marrow from 33 AML/MDS patients during post-transplant immune reconstitution, comparing those who relapsed to those who remained in remission. Persistence of recipient hematopoietic stem and progenitor cells (HSPCs) in the marrow was associated with relapse months later. These residual recipient HSPCs harbored copy number variations (CNVs), supporting their leukemic origin, and overexpressed PRAME and CALCRL compared to coexisting donor HSPCs. Further, in a subset of TP53 -mutant disease, low TCR diversity with skewing toward dominant clonotypes foreshadowed relapse. These findings lay the groundwork for improved relapse prediction and nominate therapeutic targets for early post-transplant intervention.
    DOI:  https://doi.org/10.1101/2025.11.13.688350
  10. bioRxiv. 2025 Nov 11. pii: 2025.11.10.687744. [Epub ahead of print]
    Paradoxic enhancement of mitochondrial capacity in aging-specific megakaryopoiesis from hematopoietic stem cells.
    Saran Chattopadhyaya, Stephanie Smith-Berdan, Sarah Huerta, E Camilla Forsberg.
      Aging leads to quantitative and qualitative changes in platelet (Plt) production, with increased risk for thrombosis and other adverse cardiovascular events. Recent reports showed that aging promotes the emergence of non-canonical (nc) megakaryocyte progenitors (MkPs) directly from hematopoietic stem cells (HSCs), leading to the production of hyperactive Plts. The higher engraftment potential of ncMkPs compared to both young and old canonical (c)MkPs, contrasts with the functional decline of old HSCs. Emerging reports suggest that mitochondrial function critically regulates lineage commitment and cellular functionality, but how mitochondrial activity affects aging megakaryopoiesis is unknown. Here, we demonstrate that aged MkPs sustain unique mitochondrial activity, characterized by higher mitochondrial membrane potential, higher ATP content, and lower ROS levels compared to their younger counterparts. This contrasts with the dysfunctional mitochondrial state observed in old HSCs, suggesting lineage-specific organelle adaptations upon aging. Notably, we observed that the elevated mitochondrial capacity in aged MkPs is driven selectively by the age-specific ncMkPs. Paradoxically, in vivo pharmacological enhancement of mitochondrial activity in old mice reduced in situ Plt production, but increased Plt reconstitution by transplanted HSCs. These discoveries link uniquely regulated mitochondrial capacity to the intrinsic properties of age-specific MkPs, raising the possibility of therapeutic targeting to prevent aging-induced megakaryopoiesis.
    HIGHLIGHTS: Aging-specific MkPs have elevated mitochondrial capacity, the inverse of aged HSCsMitochondrial enhancement differentially alters platelet counts in young and old miceEnhancement of mitochondrial capacity increases platelet repopulation by both young and old HSCs.
    DOI:  https://doi.org/10.1101/2025.11.10.687744
  11. Res Sq. 2025 Nov 03. pii: rs.3.rs-7956606. [Epub ahead of print]
    PRDM15 regulates differentiation and proliferation of hematopoietic stem cells.
    Ernesto Guccione, Nesteene Param, Alex Rialdi, Nayeli Guiterrez Trejo, Max Fortescue-Poole, Ke Wang, Habiba Zorgati, Daniel Lozano-Ojalvo, Magan Schwarz, Francesco Cantatore, Frank Fonseca, Kensey Portman, Kevin Mohammed, David Dominguez-Sola, Slim Mzoughi, Elvin Wagenblast.
      Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis through a tightly regulated balance of self-renewal, proliferation and differentiation, particularly under stress conditions.Here, we identify PRDM15, a transcription factor with well described roles in early embryonic development, as a crucial regulator of hematopoiesis during stress responses. While PRDM15 deletion is tolerated at steady state in adult hematopoiesis, its absence severely impairs bone marrow reconstitution following transplantation, causing sustained reduction in bone marrow cellularity and differentiation blocks. Notably, PRDM15-deleted bone marrow exhibited an accumulation of stem and progenitor cells, indicating a block in lineage differentiation. Furthermore, in competitive transplantation assays, PRDM15-deficient cells were unable to compete with wild-type counterparts, demonstrating a profound loss of fitness.Transcriptomic and epigenomic analyses reveal PRDM15 as a critical regulator of differentiation and proliferation of HSCs. Mechanistically, PRDM15 directly regulates the expression of several key genes involved in proliferation and differentiation pathways, including the transcription factor Cux1 . Cux1 overexpression partially rescues colony-forming ability of PRDM15-deficient HSCs.These findings establish PRDM15 as a pivotal stress-responsive regulator of HSC differentiation and survival, with implications for therapeutic modulation of hematopoiesis.
    DOI:  https://doi.org/10.21203/rs.3.rs-7956606/v1
  12. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2505510122
    Multipotent progenitors with distinct origins, clonal lineage fates, transcriptomes, and surface markers yield two hematopoietic trees.
    Fuwei Shang, Tamar Nizharadze, Robin Thiele, Branko Cirovic, Larissa Frank, Katrin Busch, Weike Pei, Thorsten B Feyerabend, Thomas Höfer, Xi Wang, Hans-Reimer Rodewald.
      Multipotent progenitors (MPP) are the quantitative source of native hematopoiesis that have been thought to be replenished slowly by hematopoietic stem cells (HSC). However, recent fate mapping studies have revealed two developmentally distinct populations of MPP, HSC-derived MPP (hMPP), and HSC-independent, embryonic MPP (eMPP). These data raise fundamental questions on the distinctions and functions of these progenitors. Here, we mapped the clonal dynamics of the two independent MPP systems, using in situ barcoding, and barcode linkage (hMPP), or disconnect (eMPP), with HSC. The cumulative output of eMPP to hematopoiesis was 35%, and their output was enriched for lymphoid fates. Conversely, hMPP output was enriched for myeloid-restricted fates. Distinguishing HSC from eMPP outputs revealed that only ~15% of adult HSC clones underwent multilineage differentiation (lymphoid, myeloid, and erythroid). To prospectively identify eMPP, we developed PolySMART for joint profiling of PolyloxExpress RNA barcodes, surface markers, and transcriptomes, and we found that the plasma cell marker CD138 enriches for eMPP. CD138+ MPP are primed for self-renewal and toward lymphoid fate, and become largely but not completely replaced by CD138- MPP over time, which may contribute to the loss of lymphoid output with age. Taken together, adult hematopoiesis consists of two distinct lineage trees. The source of the "eMPP tree" substantially contributes to hematopoiesis before it declines, while the HSC-hMPP tree supplies hematopoiesis life-long. Our molecular determinants distinguishing the two MPP systems may open avenues to further explore these unexpected layers of hematopoiesis.
    Keywords:  barcoding; fate mapping; layers of hematopoiesis; stem and progenitor cells; surface marker identification
    DOI:  https://doi.org/10.1073/pnas.2505510122
  13. Nat Commun. 2025 Nov 25. 16(1): 10592
    The AML cellular state space unveils NPM1 immune evasion subtypes with distinct clinical outcomes.
    Henrik Lilljebjörn, Pablo Peña-Martínez, Hanna Thorsson, Rasmus Henningsson, Marianne Rissler, Niklas Landberg, Noelia Puente-Moncada, Sofia von Palffy, Vendela Rissler, Petr Stanek, Jonathan Desponds, Xiangfu Zhong, Gunnar Juliusson, Vladimir Lazarevic, Sören Lehmann, Magnus Fontes, Helena Ågerstam, Carl Sandén, Christina Orsmark-Pietras, Thoas Fioretos.
      Acute myeloid leukemia is a genetically and cellularly heterogeneous disease. We characterize 120 AMLs using genomic and transcriptomic analyses, including single-cell RNA sequencing. Our results reveal an extensive cellular heterogeneity that distorts the bulk transcriptomic profiles. Selective examination of the transcriptional signatures of >90,000 immature AML cells identifies four main clusters, thereby extending current genomic classification of AML. Notably, NPM1-mutated AML can be stratified into two clinically relevant classes, with NPM1class I associated with downregulation of MHC class II and excellent survival following hematopoietic stem cell transplantation. NPM1class II is instead associated with resistance to allogeneic T cells in an ex vivo co-culture assay, and importantly, dismal survival following hematopoietic stem cell transplantation. These findings provide insights into the cellular state space of AML, define diagnostic entities, and highlight potential therapeutic intervention points.
    DOI:  https://doi.org/10.1038/s41467-025-66546-6
  14. Sci Transl Med. 2025 Nov 26. 17(826): eadu3313
    Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice.
    Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Prein, Timo O Odinius, Celina V Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A Dengler, Philipp J Jost.
      Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα3) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and durable remissions. LTα3 repressed leukemia by depleting tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.
    DOI:  https://doi.org/10.1126/scitranslmed.adu3313
  15. Cell Stem Cell. 2025 Nov 24. pii: S1934-5909(25)00408-4. [Epub ahead of print]
    Space-associated stem cell hallmarks of aging and resilience in astronauts.
    Jessica Pham, Shuvro P Nandi, Larisa Balaian, Claire Engstrom, Patrick Chang, Karla Mack, Inge van der Werf, Emma Klacking, Jenna Sneifer, Neha Katragadda, Kendale Wirtjes, Antonio Ruiz, Daisy Chilin-Fuentes, Elsa Molina, Pinar Mesci, Jana Stoudemire, Sheldon R Morris, Thomas Whisenant, Ludmil B Alexandrov, Catriona H M Jamieson.
      Previous reports revealed immune dysfunction, chromosomal abnormalities, cytokine deregulation, and telomere alterations after prolonged spaceflight. However, the stress of space on hematopoietic stem and progenitor cells (HSPCs) and the resilience properties maintaining lifelong hematopoiesis and immunity were not studied. We performed HSPC functionally organized multi-omics aging and resilience (HSPC-FOMA-R) analyses in 9 astronauts before, during, and after three short-duration International Space Station (ISS) missions. Whole-genome sequencing (with telomere length analysis and mitochondrial and clonal mutational profiling), whole-transcriptome sequencing (with RNA editing and retrotransposon analyses), single-cell RNA sequencing, cytokine arrays, and fluorescence-activated cell sorting (FACS) analyses assessed HSPC and immune subpopulation survival dynamics. We show that spaceflight is associated with partially reversible changes in HSPC survival and self-renewal, adenosine deaminase associated with RNA1 (ADAR1), telomere maintenance, mobilization, cell cycle, and "fight or flight" gene expression. Combined with clonal hematopoietic mutations, apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3C) activation, and retrotransposon deregulation, HSPC-FOMA-R analyses are needed before extended missions.
    Keywords:  ADAR1; APOBEC3C; astronauts; clonal mutations; hematopoietic stem and progenitor cells; mitochondria; resilience; retrotransposons; spaceflight; telomere
    DOI:  https://doi.org/10.1016/j.stem.2025.11.001
  16. Nature. 2025 Nov 26.
    Inhibitors supercharge kinase turnover through native proteolytic circuits.
    Natalie S Scholes, Martino Bertoni, Arnau Comajuncosa-Creus, Katharina Kladnik, Xuefei Guo, Fabian Frommelt, Matthias Hinterndorfer, Hlib Razumkov, Polina Prokofeva, Martin P Schwalm, Florian Born, Sandra Roehm, Hana Imrichova, Brianda L Santini, Eleonora Barone, Caroline Schätz, Miquel Muñoz I Ordoño, Severin Lechner, Andrea Rukavina, Iciar Serrano, Miriam Abele, Anna Koren, Stefan Kubicek, Stefan Knapp, Nathanael S Gray, Giulio Superti-Furga, Bernhard Kuster, Yigong Shi, Patrick Aloy, Georg E Winter.
      Targeted protein degradation is a pharmacological strategy that relies on small molecules such as proteolysis-targeting chimeras (PROTACs) or molecular glues, which induce proximity between a target protein and an E3 ubiquitin ligase to prompt target ubiquitination and proteasomal degradation1. Sporadic reports indicated that ligands designed to inhibit a target can also induce its destabilization2-4. Among others, this has repeatedly been observed for kinase inhibitors5-7. However, we lack an understanding of the frequency, generalizability and mechanistic underpinnings of these phenomena. Here, to address this knowledge gap, we generated dynamic abundance profiles of 98 kinases after cellular perturbations with 1,570 kinase inhibitors, revealing 160 selective instances of inhibitor-induced kinase destabilization. Kinases prone to degradation are frequently annotated as HSP90 clients, therefore affirming chaperone deprivation as an important route of destabilization. However, detailed investigation of inhibitor-induced degradation of LYN, BLK and RIPK2 revealed a differentiated, common mechanistic logic whereby inhibitors function by inducing a kinase state that is more efficiently cleared by endogenous degradation mechanisms. Mechanistically, effects can manifest by ligand-induced changes in cellular activity, localization or higher-order assemblies, which may be triggered by direct target engagement or network effects. Collectively, our data suggest that inhibitor-induced kinase degradation is a common event and positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.
    DOI:  https://doi.org/10.1038/s41586-025-09763-9
  17. Cell Rep. 2025 Nov 25. pii: S2211-1247(25)01374-9. [Epub ahead of print]44(12): 116602
    Harnessing the E3 ligase SPOP for targeted degradation of the NUP98::KDM5A fusion oncoprotein.
    Ecem Kirkiz, Gabriel Kaufmann, Simone Bergqvist, Pablo Fernández-Pernas, Thomas Eder, Laura Quell, Melanie Allram, Gabriele Manhart, Wencke Walter, Torsten Haferlach, Florian Grebien.
      Nucleoporin 98-rearranged (NUP98-r) acute myeloid leukemia (AML) is associated with poor outcomes and remains a major therapeutic challenge due to the absence of strategies that directly eliminate NUP98 fusion oncoproteins. Targeted degradation of cancer-driving oncofusions is an attractive approach, but the molecular mechanisms controlling NUP98 oncofusion stability are unknown. Using a CRISPR-Cas9 screen, we identify the E3 ligase Speckle-type POZ protein (SPOP) as a direct regulator of NUP98 fusion oncoprotein stability and a novel tumor suppressor in NUP98-r AML. Loss of SPOP increases NUP98 oncofusion levels and promotes leukemia cell proliferation. Exploiting this specificity, we demonstrate that induced proximity of SPOP and NUP98::lysine-specific demethylase 5A (KDM5A) through a biological proteolysis-targeting chimera (bioPROTAC) induces full clearance of the fusion oncoprotein, driving terminal differentiation and apoptosis of NUP98-r leukemia cells in vitro and in vivo. This study identifies SPOP as a direct regulator of NUP98 oncofusion stability and outlines a strategy to redirect the ubiquitin-proteasome system against oncogenic fusions.
    Keywords:  AML; CP: cancer; NUP98; PROTAC; SPOP; condensate; fusion protein; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116602
  18. Nat Commun. 2025 Nov 28. 16(1): 10743
    TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
    Nandini Shukla, Maxwell L Neal, Jean-Claude Farré, Fred D Mast, Rajasri Sarkar, Linh Truong, Theresa Simon, Leslie R Miller, John D Aitchison, Suresh Subramani.
      Peroxisomes are versatile organelles mediating energy homeostasis and redox balance. While peroxisome dysfunction is linked to numerous diseases, the mechanisms regulating peroxisome dynamics during cellular stress remain elusive. Using yeast, we show that proteotoxic stress, including loss of endoplasmic reticulum (ER) or cytosolic chaperone function, impaired ER protein translocation, disrupted N-linked glycosylation, or reductive stress, triggers peroxisome proliferation. This occurs through increased de novo biogenesis from the ER, as well as growth and division, rather than impaired pexophagy. Peroxisome biogenesis is essential for cellular recovery from proteotoxic stress. Through comprehensive testing of major signaling pathways, we determine this response to be mediated by activation of the heat shock response and inhibition of Target of Rapamycin (TOR) signaling. Notably, the effects of proteotoxic stress and TOR inhibition on peroxisomes are also observed in human fibroblasts. Our findings reveal a critical and conserved role of peroxisomes in cellular response to proteotoxic stress.
    DOI:  https://doi.org/10.1038/s41467-025-65776-y
  19. Biochem Biophys Res Commun. 2025 Nov 18. pii: S0006-291X(25)01718-8. [Epub ahead of print]793 153002
    Development of a CRISPR/Cas9-degron system that enables in vivo specific gene depletion in leukemia models.
    Ruka Shimura, Keita Yamamoto, Yu-Hsuan Chang, Aika Otaki, Susumu Goyama.
      The CRISPR/Cas9 system has transformed genome editing, yet precise temporal control of Cas9 activity remains challenging. We developed a Cas9-degron platform that couples degron-tagged Cas9 with a dTAG-based chemical degradation strategy. In the presence of dTAG, Cas9 is rapidly and near-completely degraded, preventing editing; upon dTAG withdrawal, Cas9 activity is restored, enabling precise temporal control. Using this system, we achieved selective in vivo gene depletion in acute myeloid leukemia (AML) models and confirmed that SETDB1, a histone H3K9 methyltransferase, is essential for the in vivo growth of both human (MOLM13) and murine (cSAM) AML cells. By maintaining SETDB1 intact prior to transplantation and depleting it afterward, we avoided culture-induced pre-selection bias inherent to sgRNA transduction and validated its critical role in AML progression within the in vivo context. The Cas9-degron retains activity and delivery efficiency comparable to conventional Cas9 in the absence of dTAG. Thus, this versatile system provides a superior alternative to conventional Cas9 and a powerful platform for in vivo CRISPR screening, gene function studies, and potentially temporally controlled gene therapy.
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153002
  20. Nat Commun. 2025 Nov 27. 16(1): 10690
    Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.
    Susanna Eli, Greta Rauso, Paola Ghezzi, James L A Szczerkowski, Michela Bruzzi, Francesca Rizzelli, Fabiola Iommazzo, Alessia Loffreda, Francesco Castagna, Federico Donà, Chiara Gaddoni, Ambra Dondi, Mattia Marenda, Simona Rodighiero, Pierre Tournier, Zeno Lavagnino, Dario Parazzoli, Nils C Gauthier, Simone Tamburri, Diego Pasini, Shukry James Habib, Marina Mapelli.
      In multicellular organisms, the execution of developmental and homeostatic programs often relies on asymmetric cell divisions. These divisions require the alignment of the mitotic spindle axis to cortical polarity cues, and the unequal partitioning of cellular components between progeny cells. Asymmetric divisions are orchestrated by signals from the niche frequently presented in a directional manner, such as Wnt signals. Here we employ bioengineered Wnt-niches to demonstrate that in metaphase NuMA/dynein microtubule motors form a complex with activated LRP6 and β-catenin at the cortical sites of Wnt activation to orient cell division perpendicularly. We show that engagement of LRP6 co-receptors by Wnt ligands locally stabilizes actomyosin contractility through the accumulation of myosin1C. Additionally, we describe a proteomic-based approach to identify mitotic protein complexes enriched at the Wnt-contact site, revealing that mitochondria polarize toward localized Wnt3a sources and are asymmetrically apportioned to the Wnt-proximal daughter cell during Wnt-mediated asymmetric cell division of embryonic stem cells. Mechanistically, we show that CENP-F is required for mitochondria polarization towards localized sites of Wnt3a activation, and that deletion of the Wnt-co-receptor LRP6 impairs the asymmetric apportioning of mitochondria. Our findings enhance the understanding of mitotic Wnt-signaling and elucidate fundamental principles underlying Wnt-dependent mitochondrial polarization.
    DOI:  https://doi.org/10.1038/s41467-025-65775-z
  21. Nat Commun. 2025 Nov 26. 16(1): 10591
    NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms.
    Ruth-Miriam Koerber, Calvin Krollmann, Kevin Cieslak, Elisabeth Tregel, Maria L Saenz, Tim H Brümmendorf, Steffen Koschmieder, Martin Griesshammer, Ines Gütgemann, Conny K Baldauf, Thomas Fischer, Peter Brossart, Carl Christian Kolbe, Eicke Latz, Dominik Wolf, Lino L Teichmann.
      The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigate whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevents increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promotes excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promotes expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhances bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease leads to regression of thrombocytosis, splenomegaly and bone marrow fibrosis. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.
    DOI:  https://doi.org/10.1038/s41467-025-65673-4
  22. Haematologica. 2025 Nov 27.
    A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity.
    Amit K Jaiswal, Georgia M Scherer, Michelle L Thaxton, Jacob P Sorrentino, Constance Yuen, Milauni M Mehta, Gunjan Sharma, Tasha L Lin, Tiffany M Tran, Amanda Cohen, Alexander J Ritter, Rishi S Kotecha, Jeremy R Sanford, Robert D Damoiseaux, Neil K Garg, Dinesh S Rao.
      The RNA-binding protein IGF2BP3 is an oncofetal protein overexpressed in B-acute lymphoblastic leukemia and is critical for leukemogenesis in experimental models. With cancerspecific expression, functional dispensability for normal development, and an unleveraged prooncogenic function in mRNA homeostasis, IGF2BP3 represents an excellent target. With no small molecule inhibitors of IGF2BP3 in clinical use, we undertook an effort to identify new IGF2BP3 inhibitors using biochemical methods. A biochemical screen, followed by a cell-based counter screen, led to the identification of compounds with protein-RNA interaction inhibition and leukemic cell growth-inhibitory activity. One of these compounds, designated I3IN-002, shows consistent cell growth-inhibitory activity, altered cell cycle and increased apoptosis in multiple leukemia cell lines, and is the most potent inhibitor of IGF2BP3 reported to date. I3IN- 002 was tolerated in mice when administered intraperitoneally and showed potent anti-leukemic activity in a syngeneic transplantation model of MLL-Af4 leukemia. I3IN-002 inhibits the function of IGF2BP3, disrupting in situ binding of IGF2BP3 to target mRNAs, and altering IGF2BP3- dependent gene expression regulation. Furthermore, cell-free and cellular thermal shift assays as well as drug affinity responsive target stability assays support on target activity of I3IN-002 for IGF2BP3. Thus, the identification of I3IN-002 paves the way for the discovery of potent and selective small molecule inhibitors of IGF2BP3.
    DOI:  https://doi.org/10.3324/haematol.2025.288221
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