bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–12–14
twenty papers selected by
William Grey, University of York
  1. Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.
  2. Tumor necrosis factor from leukemic environment stimulates hematopoietic stem / progenitor cells toward megakaryocyte / myeloid lineage bias.
  3. Prospective isolation of mouse and human hematopoietic stem cells using PLXDC2.
  4. Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling.
  5. Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops.
  6. Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.
  7. Potency of human hematopoietic cells from a novel CD34+ isolation technique.
  8. Unraveling hematopoietic stem cell ontogeny through single-cell multi-omics approaches.
  9. A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia.
  10. Mechanometabolism instructs hematopoietic stem cell specification.
  11. Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response.
  12. A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy.
  13. Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.
  14. Structural basis of microtubule-mediated signal transduction.
  15. Oncostatin M induced by STAT5-activating oncogenes promotes disease progression in hematologic malignancies.
  16. Mixed-lineage leukaemia cells undergo unique adaptations in the CNS niche.
  17. Unifying proteomic technologies with ProteinProjector.
  18. Elevated SUN1 promotes migratory cell polarity defects through mechanically coupling microtubules to the nuclear lamina.
  19. The inhibition of de novo purine synthesis increases LAMP2 expression to preserve cell viability.
  20. CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.
  1. bioRxiv. 2025 Dec 01. pii: 2025.11.27.690982. [Epub ahead of print]
    Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.
    Fanny J Zhou, Michelle K Le, Helen C Wang, Wei Yang, Huan-You Wang, Arukshita Tiwari, Xinjian Cen, Mary Jean Sunshine, Jeffrey A Magee, Robert A J Signer.
      Aging is the primary risk factor for clonal hematopoiesis and the development of hematologic malignancies ( 1-5 ), yet the selective pressures that shape stem cell behavior and clonal expansion during aging remain poorly defined. Here, we identify proteostasis stress as a central driver of hematopoietic stem cell (HSC) aging and clonal evolution. We show that Heat shock factor 1 (Hsf1) is activated in aging HSCs to preserve proteostasis and sustain self-renewal. However, this physiological, age-associated adaptive mechanism is co-opted by pre-leukemic Dnmt3a -mutant HSCs to resist proteostasis and inflammatory stress required to fuel clonal expansion during aging. In the context of co-occurring Dnmt3a and Nras mutations, which are frequently observed in human acute myeloid leukemia (AML) ( 6-13 ), mutant HSCs and progenitors exhibit heightened dependence on Hsf1 for expansion, malignant transformation and disease progression. Loss of Hsf1 , or disruption of proteostasis, impairs expansion of mutant progenitors, delays leukemia onset, and prolongs survival. Together, these findings reveal proteostasis as a key constraint in the aging hematopoietic system that imposes a selective bottleneck. Hsf1 activation enables both physiological adaptation in aging stem cells and pathological clonal outgrowth in pre-leukemic and leukemic states, establishing proteostasis control as a pivotal mechanism linking stem cell aging to clonal hematopoiesis and malignancy.
    DOI:  https://doi.org/10.1101/2025.11.27.690982
  2. Exp Hematol. 2025 Dec 04. pii: S0301-472X(25)00621-6. [Epub ahead of print] 105332
    Tumor necrosis factor from leukemic environment stimulates hematopoietic stem / progenitor cells toward megakaryocyte / myeloid lineage bias.
    Hidekazu Nishikii, Riko Kikuchi, Takaharu Kimura, Mizuki Saito, Yusuke Kiyoki, Saki Tanaka, Yamato Sasaki, Takayasu Kato, Tatsuhiro Sakamoto, Mamiko Sakata-Yanagimoto, Naoshi Obara, Satoshi Yamazaki, Shigeru Chiba.
      Acute myeloid leukemia (AML) is characterized by the proliferation of malignant myeloid progenitor cells and impairment of hematopoiesis. Although genetic abnormalities within leukemic cells have been investigated in detail, definitive explanations for the damage to the normal hematopoietic system are lacking. Here, we investigated the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow in AML. We evaluated the function of residual non-leukemic (nl)-hematopoietic stem / progenitor cell (HSPC) from the bone marrow of mice with MLL-AF9-induced AML. The nl-HSPC in the leukemic marrow showed a megakaryocyte (MgK) and myeloid-biased gene expression signature, with enrichment of TNF signaling and reduced repopulation ability. To investigate whether the upregulation of TNF signaling causes the MgK / myeloid lineage bias, we investigated the effects of TNF-α in normal hematopoietic stem cells (HSC) / HSPC under ex-vivo expansion condition. Single-cell transcriptome analysis of these cells revealed an increased frequency of cells expressing genes related to the MgK lineage and decreased repopulation capacity compared with those of ex vivo-expanded HSC / HSPC without TNF-α. Our data suggest that increased TNF-α in the leukemic bone marrow environment at least in part drives HSPC toward MgK / myeloid differentiation, resulting in the exhaustion of residual normal HSC / HSPC. These findings offer valuable insights into leukemic biology and normal hematopoiesis.
    Keywords:  Acute myeloid leukemia; bone marrow environment; hematopoietic stem progenitor cells; tumor necrosis factor
    DOI:  https://doi.org/10.1016/j.exphem.2025.105332
  3. Commun Biol. 2025 Dec 10.
    Prospective isolation of mouse and human hematopoietic stem cells using PLXDC2.
    Yosuke Tanaka, Yasushi Kubota, Riko Kikuchi, Tomohiro Yabushita, Takaharu Kimura, Ivo Lieberam, Jillian L Barlow, Josh W Bramley, Tsuyoshi Fukushima, Chiaki Sakuma, Takashi Shibata, Masataka Nakagawa, Yasunori Kurosawa, Toshiaki Maruyama, C J Okumura, Yuichiro Arima, Yoshinori Sato, Yasuo Ono, Teruo Akuta, Hidenobu Mizuno, David G Kent, Thomas M Jessell, Susumu Goyama, Hidekazu Nishikii, Shinya Kimura, Satoshi Yamazaki, Toshio Suda, Toshio Kitamura.
      Numerous strategies exist to isolate hematopoietic stem cells (HSCs) using complex combinations of markers and flow cytometry. However, robust identification of HSCs using imaging techniques is substantially more challenging which has prompted the recent development of HSC reporter mice. To date, very few molecules used in these reporters have been useful for human HSC identification. Here we report that PLXDC2 is a useful marker for both mouse and human cord blood HSCs. Using a green fluorescent protein (GFP) knock-in at the Plxdc2 locus in mice (hereafter denoted as Plxdc2-GFP), we showed that Plxdc2-GFP is highly expressed in HSCs with 1 in 2.8 Plxdc2-GFP+CD150+ cells giving long-term multi-lineage reconstitution in transplantation. Moreover, we developed a novel human PLXDC2 antibody and showed that human PLXDC2+ HSCs have higher long-term multilineage reconstitution ability compared with PLXDC2- HSCs in a xenograft model. This study identifies PLXDC2 as a highly relevant molecule in HSC identification.
    DOI:  https://doi.org/10.1038/s42003-025-09242-x
  4. Blood Adv. 2025 Dec 09. pii: bloodadvances.2025016400. [Epub ahead of print]
    Elevated Lactate in AML Bone Marrow Contributes to Macrophage Polarization via GPR81 Signaling.
    Celia A Soto, Maggie L Lesch, Jennifer L Becker, Azmeer Sharipol, Amal Khan, Xenia L Schafer, Zhewen Li, Amanda R Streeter, Michael W Becker, Joshua C Munger, Benjamin J Frisch.
      Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016400
  5. Cell Rep. 2025 Dec 06. pii: S2211-1247(25)01422-6. [Epub ahead of print]44(12): 116650
    Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops.
    Yinghao Pan, Hongna Zuo, Xianjin Yan, Jiali Li, Yuwen Li, Jin Li, You Wu, Liquan Hong, Mingwei Wang, Aiwei Wu, Zhenyu Ju, Yawei Gao, Hu Wang.
      Pervasive transcription of the mammalian genome produces a vast repertoire of non-functional nascent transcripts, generating R loops and R-loop-induced DNA breaks. Such a coupling between continual transcription and a burst of R-loop formation, however, presents a challenge for hematopoietic stem cells (HSCs) to maintain their genome integrity. Here, we show that the nuclear exosome targeting (NEXT) complex, an RNA adaptor that targets non-functional nascent transcripts to the RNA exosome for decay, plays a pivotal role in overcoming this challenge. Hematopoietic-specific deletion of ZCCHC8, a core subunit of NEXT, not only leads to impaired HSC self-renewal but also causes elevated DNA lesions and upregulated DNA repair pathways in HSCs due to accumulated R loops. Moreover, dysregulation of ZCCHC8 occurs frequently in diffuse large B cell lymphoma (DLBCL) and is associated with poor clinical outcomes. Collectively, our findings highlight NEXT as a novel protector of HSCs and position it as a potential therapeutic target for DLBCL.
    Keywords:  CP: molecular biology; CP: stem cell research; DNA damage; NEXT complex; hematopoietic stem cells; lymphoma; self-renewal; transcription-coupled R loops
    DOI:  https://doi.org/10.1016/j.celrep.2025.116650
  6. Cancer Discov. 2025 Dec 06. OF1-OF30
    Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.
    BDRL
      Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98::NSD1-driven pediatric acute myeloid leukemia that is particularly aggressive with WT1 comutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.
    SIGNIFICANCE: This study signifies the critical consequences of developmental timing in cancer initiation, revealing that identical driver mutations in fetal- versus postnatal-origin leukemias exhibit fundamentally distinct biology and treatment responses. Recognizing these developmental differences opens avenues for personalized therapeutic strategies, improving outcomes for pediatric patients with aggressive disease subtypes in leukemia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0556
  7. Stem Cells Transl Med. 2025 Nov 24. pii: szaf067. [Epub ahead of print]14(12):
    Potency of human hematopoietic cells from a novel CD34+ isolation technique.
    James Ropa, Jimin Park, Jessica Newton, So Jeong Kim, Yangshin Park, Jonathan Messer, Justin Blacher, Shabnam Namin.
      Hematopoietic stem and progenitor cells are responsible for maintenance of the immune system and can be a source of cells for therapies. A critical step in studying or utilizing hematopoietic cells is subpopulation isolation. FerroBio is an emerging technology that uses a streamlined, semi-automated approach to isolate CD34+ cells, which are highly enriched for hematopoietic stem and progenitors. This technology also results in isolation of bead-free CD34+ cell samples, in contrast to traditional kits where beads persist following isolation. Here, we showed a side-by-side comparison of FerroBio isolated cells with CD34+ cells isolated by traditional column-based kits. We showed that FerroBio yields similar numbers of CD34+ cells with similar viability, yield, and gated purity and higher overall purity compared to control kits. FerroBio isolated similar numbers of progenitor cells but significantly higher stem cells. Ex vivo, cells isolated by FerroBio showed the same ability to form colonies in culture, but FerroBio colony-forming units expanded to a greater extent in liquid culture compared to control. Critically, FerroBio isolated cells had equivalent long-term engraftment capacity with significantly better intermediate-term engraftment compared to control in mouse models of transplantation. Based on microscopy images showing altered morphology co-localized with beads, we inferred that the persistence of magnetic microbeads may be associated with the observed differences. These data demonstrated that specific subpopulations of progenitors from FerroBio isolated CD34+ cells have better potency compared to cells isolated with column-based kits. Thus, FerroBio is a viable strategy for isolating CD34+ cells for research and potentially translational utility.
    Keywords:  CD34+; cell isolation; hematopoietic stem and progenitor cells; mouse models; potency
    DOI:  https://doi.org/10.1093/stcltm/szaf067
  8. Front Cell Dev Biol. 2025 ;13 1704887
    Unraveling hematopoietic stem cell ontogeny through single-cell multi-omics approaches.
    Yan Jia, Sixuan Huo, Fei Wu, Ningning Song, Mei Li.
      Definitive hematopoietic stem cells (HSCs) originate de novo within the vertebrate aorta-gonad-mesonephros (AGM) region via endothelial-to-hematopoietic transition (EHT) from hemogenic endothelial cells (HECs). The application of single-cell multi-omics has significantly deepened our knowledge about hematopoietic development. In this review, we focus on the ontogeny of HSCs and summarize novel insights gained from single-cell omics studies. These include newly identified components of hematopoietic regulatory networks, the cellular heterogeneity during HSC generation, innovative strategies for enriching rare cell subpopulations, and newfound knowledge about the AGM microenvironment. In the concluding section, we discuss key unresolved questions related to in vivo generation and in vitro induction of HSCs, while exploring the potential of single-cell omics to propel future research in this field.
    Keywords:  aorta-gonad-mesonephros (AGM) region; developmental heterogeneity; endothelial-to-hematopoietic transition (EHT); hematopoietic stem cells (HSCs); single-cell multi-omics
    DOI:  https://doi.org/10.3389/fcell.2025.1704887
  9. Leukemia. 2025 Dec 12.
    A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia.
    Nadine E Struckman, Georgia Koutsoumpli, Rob C M de Jong, Dyantha I van der Lee, Dennis F G Remst, Sophie-Anne I Smith, M Willy Honders, Renate S Hagedoorn, Arnoud H de Ru, Masashi Matsuda, Fumihiko Ishikawa, Tamar Tak, Peter J M Valk, Mirjam H M Heemskerk, Peter A van Veelen, J H Frederik Falkenburg, Marieke Griffioen.
      Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. RUNX1 mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of RUNX1-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with RUNX1-mutated AML.
    DOI:  https://doi.org/10.1038/s41375-025-02817-x
  10. J Exp Med. 2026 Mar 02. pii: e20250607. [Epub ahead of print]223(3):
    Mechanometabolism instructs hematopoietic stem cell specification.
    Paulina D Horton, Alina Syed, Michelle Winkler, Abishek B Vaidya, Michael Rariden, Neha Arora, Yong Zhou, Michihiro Kobayashi, Momoko Yoshimoto, Hyun Jung Lee, Hyun-Eui Kim, John P Hagan, Catherine Denicourt, Travis I Moore, Pamela L Wenzel.
      Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. Flow-responsive metabolic reprogramming depends upon mechanistic target of rapamycin (mTOR) activation and is stymied when ribosome activity or mTOR is blocked. Conversely, chemical induction of mTOR mimics the effects of force on mitochondria and blood reconstituting potential and also partially rescues hematopoiesis in heartbeat mutants in utero. These findings identify mechanometabolism as a determinant of hematopoietic fate that could inform engineering of HSCs for disease modeling and treatment.
    DOI:  https://doi.org/10.1084/jem.20250607
  11. Haematologica. 2025 Dec 11.
    Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response.
    Andrej Besse, Marianne Kraus, Tiberiu Totu, Marija Buljan, Antonius P A Janssen, Mario Van der Stelt, Karin Matisikova, Jana Veprkova, Lenka Sedlarikova, Tamara Jurinakova, Marietta Truger, Claudia Haferlach, Max Mendez Lopez, Martin K Kortum, Leo Rasche, Christoph Driessen, Lenka Besse.
      Proteasome inhibitor (PI) resistance remains a major therapeutic obstacle in the treatment of multiple myeloma (MM). MM cells demonstrate pronounced dependence on insulin and insulin-like growth factor-1 signaling via their cognate receptors, IGF-1R and INSR. In this study, we identify ceritinib, a clinically approved inhibitor of anaplastic lymphoma kinase (ALK), as a drug, which can inhibit IGF-1R/INSR activity and downstream PI3K/AKT/mTORC1 signaling. Ceritinib can overcome PI-resistance in MM when used in combination with carfilzomib. This synergy was consistently observed across in vitro and in vivo models, and primary patient-derived MM cells. Mechanistically, MM cells exploit IGF- 1R/INSR signaling to sustain expression of key molecular chaperones, including HSP70 and BiP, which are critical for maintaining proteostasis under conditions of high protein synthesis and turnover. Pharmacological inhibition of IGF-1R/INSR signaling by ceritinib abrogates this adaptive stress response, thereby preventing the upregulation of cytoprotective heat shock proteins upon proteasome inhibition. This disruption results in enhanced accumulation of protein aggregates, increased protein polyubiquitination, endoplasmic reticulum stress, and activation of apoptotic pathways. Collectively, our findings support the repurposing of ceritinib in combination with carfilzomib as a translationally relevant and safe strategy to circumvent PI resistance in MM, warranting further clinical investigation in the relapsed/refractory disease setting.
    DOI:  https://doi.org/10.3324/haematol.2025.289245
  12. bioRxiv. 2025 Nov 26. pii: 2025.11.24.690135. [Epub ahead of print]
    A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy.
    Vishnu Suresh Babu, Sayan Ghosh, Sridhar Bammidi, Ryu Jiwon, Ruchi Sharma, Dominique Meyer, Stacey Hose, Padmanabhan P Pattabiraman, José-Alain Sahel, Nathan J Kidley, Natércia F Braz, Martin J Slater, Stuart Lang, Arkasubhra Ghosh, Ji Yi, Srinivasa Sripathi, Kannan Rangaramanujam, Kapil Bharti, Debasish Sinha.
      Protein kinases canonically suppress autophagy, yet how cells activate autophagy during stress remains unclear. Here we reveal that AKT1 kinase promotes autophagy through a non-canonical pathway. AKT2 loss triggers compensatory AKT1 activation, which phosphorylates telomerase reverse transcriptase (TERT) at Serine 824, driving nuclear translocation. Nuclear TERT assembles with FOXO3 and c-MYC into a transcriptional complex that activates PERK, initiating a feed-forward loop. PERK-ATF4 signaling amplifies autophagy gene transcription while inducing selective ERphagy through receptors TEX264 and CCPG1. Using C. elegans , mouse models, and human iPSCs, we demonstrate this AKT1-TERT-c-MYC-FOXO3 axis is evolutionarily conserved and essential for proteostasis in post-mitotic cells. We developed a first-in-class allosteric AKT2 inhibitor through structure-guided design that selectively triggers beneficial AKT1 compensation, restoring autophagy in diseased cells. These findings reveal a transcriptional mechanism linking AKT1 activation to autophagy and provide a therapeutic strategy for diseases with defective ER quality control.
    DOI:  https://doi.org/10.1101/2025.11.24.690135
  13. Haematologica. 2025 Dec 11.
    Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.
    Shanna M Hogeling, Dominique Sternadt, Nikita La Rose, Marjan Geugien, Diego Pereira-Martins, Fiona A J Van den Heuvel, Anna Kuchnio, Christine E Pietsch, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa.
      Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing to explore alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal cocultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial ROS and lipid peroxidation. LC-MS/MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids (PUFAs) and triglycerides (TGs), which are the primary lipid species stored in lipid droplets (LDs). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LDs. Indeed, we could observed a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was upregulated in DHODHi sensitive AMLs, and a strong synergy was observed between combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that combined DHODH and SREBP inhibition is of interest to explore further as a therapeutic target option in AML.
    DOI:  https://doi.org/10.3324/haematol.2025.287918
  14. Cell. 2025 Dec 08. pii: S0092-8674(25)01307-8. [Epub ahead of print]
    Structural basis of microtubule-mediated signal transduction.
    Sung Ryul Choi, Thorsten B Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D Gossert, G V Shivashankar, Alfred Zippelius, Michel O Steinmetz.
      Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.
    Keywords:  cytoskeleton; microtubules; molecular mechanism; signal transduction; signaling proteins; structure-function relationship
    DOI:  https://doi.org/10.1016/j.cell.2025.11.011
  15. Signal Transduct Target Ther. 2025 Dec 11. 10(1): 400
    Oncostatin M induced by STAT5-activating oncogenes promotes disease progression in hematologic malignancies.
    Michael Rassner, Tony Andreas Müller, Kirstyn Anne Crossley, Geoffroy Andrieux, Sabina Schaberg, Cornelia Endres, Lena Jakob, Teresa Poggio, Natalie Köhler, Julia Kolter, Gerhard Müller-Newen, Katharina Schönberger, Nina Cabezas-Wallscheid, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Melissa Zwick, Driti Ashok, Tanja Nicole Hartmann, Olaf Groß, Oliver Gorka, Marie Follo, Anna Lena Illert, Melanie Boerries, Robert Zeiser, Justus Duyster.
      Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies. We found that the STAT5-activating oncogenes JAK2 p.V617F, FLT3-ITD, and BCR::ABL1 induce oncostatin M (OSM), which triggers disease progression and immunosuppression. The OSM receptor was predominantly expressed on nonhematopoietic bone marrow (BM) stromal cells. OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion, including IL-6 and MCP-1. Compared with control mice, OSM-overexpressing mice presented reduced T-cell numbers, increased levels of inhibitory receptors on T cells, and elevated lactic acid production by BM stromal cells. OSM induced the expansion of myeloid cells which suppressed T cells. Conversely, genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia, BM fibrosis, inflammatory cytokine levels and the expression of inhibitory markers on T cells. Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6-JAK-STAT3 and inflammatory signaling pathways. Additionally, pharmacological inhibition of OSM reduced disease activity and cytokine production. These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression. Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.
    DOI:  https://doi.org/10.1038/s41392-025-02491-6
  16. Exp Hematol. 2025 Dec 08. pii: S0301-472X(25)00626-5. [Epub ahead of print] 105347
    Mixed-lineage leukaemia cells undergo unique adaptations in the CNS niche.
    Alasdair Duguid, Camille Malouf, Leslie Nitsche, Chris Halsey, Katrin Ottersbach.
      KMT2A-rearranged (KMT2A-r) infant leukaemia can present as a lymphoid, myeloid or mixed-lineage leukaemia and frequently involves the central nervous system (CNS), yet the impact of this lineage diversity and plasticity on CNS involvement remains poorly understood. Using a fully murine immunocompetent model of KMT2A-AFF1+ mixed-lineage infant leukaemia, we investigated how the CNS niche influences the phenotype and function of leukaemia propagating cells (LPC). Previously defined bone marrow (BM)-derived LPCs were transplanted and shown to engraft the CNS, although not equally; lineage-negative cKit+ common lymphoid progenitor cells were consistently underrepresented in the niche. Transplants of CNS-derived LPCs, modelling relapse, demonstrated reduced systemic repopulation capacity, with many recipients exhibiting stable long-term engraftment without developing overt leukaemia, a phenomenon not observed in BM-derived transplants. Transcriptomic profiling of matched CNS- and BM-derived LPCs revealed enrichment of pathways involved in hypoxia, lipid and cholesterol homeostasis, and inflammatory signalling in the CNS. Notably, LPC subsets that successfully adapted to the CNS niche upregulated lipid and fatty acid metabolic programmes. CNS-derived LPCs showed increased expression of genes involved in T cell immune modulation, suggesting a skew to a more immunosuppressive environment. These findings indicate that the CNS niche imposes selective pressures that cause lasting metabolic and functional reprogramming of leukemic cells, impairing their ability to reestablish systemic disease and potentially affecting immune cell interactions. Furthermore, these findings may be more generally relevant to primary mixed-lineage infant leukaemia and, increasingly important, lineage-switched infant leukaemia.
    Keywords:  KMT2A-AFF1; central nervous system; immune microenvironment; infant leukaemia; microRNA; mixed-lineage leukaemia
    DOI:  https://doi.org/10.1016/j.exphem.2025.105347
  17. Bioinform Adv. 2025 ;5(1): vbaf266
    Unifying proteomic technologies with ProteinProjector.
    Leah V Schaffer, Mayank Jain, Rami Nasser, Roded Sharan, Trey Ideker.
       Summary: Proteomics has developed many approaches to inform the subcellular organization of proteins, each with differing coverage and sensitivity to distinct scales. Here, we develop a self-supervised deep learning framework, ProteinProjector, that flexibly integrates all available data for a protein from any number of modalities, resulting in a unified map of protein position. As initial proof-of-concept we integrate four proteome-wide characterizations of HEK293 human embryonic kidney cells, including protein affinity purification, proximity ligation, and size-exclusion-chromatography mass spectrometry (AP-MS, PL-MS, SEC-MS), as well as protein fluorescent imaging. Map coverage and accuracy grow substantially as new data modes are added, with maximal recovery of known complexes observed when using all four proteomic datasets. We find that ProteinProjector outperforms individual modalities and other integration methods in recovery of orthogonal functional and physical associations not used during training. ProteinProjector provides a foundation for integration of diverse modalities that characterize subcellular structure.
    Availability and implementation: ProteinProjector is available as part of the Cell Mapping Toolkit at https://github.com/idekerlab/cellmaps_coembedding.
    DOI:  https://doi.org/10.1093/bioadv/vbaf266
  18. Commun Biol. 2025 Dec 09.
    Elevated SUN1 promotes migratory cell polarity defects through mechanically coupling microtubules to the nuclear lamina.
    Yutao Li, Yicong Zhang, Mengqi Chen, Susumu Antoku, Junjun Ding, Kaiyao Huang, Gregg G Gundersen, Wakam Chang.
      In migratory fibroblasts, front-rear polarity is defined by the centrosome positioned anterior to a rearward nucleus. To achieve this polarity, actin cables couple to nuclear membrane proteins nesprin-2G and SUN2 and drive the nucleus backward. Aging disrupts this polarity by increasing SUN1, a SUN2 homolog. Here, we investigated the molecular mechanisms behind this disruption and found that the dominant-negative effect of SUN1 and progerin, a lamin A variant, required direct SUN1-lamin A interaction. Microtubule interaction and force transmission through a nesprin, identified as nesprin-2, are crucial for SUN1's effect. We further discovered that stable microtubules are both necessary and sufficient to inhibit cell polarity. Using SUN1-SUN2 chimeric proteins, we demonstrated that the SUN domains determine their roles in cell polarization. Our findings reveal how elevated SUN1 disrupts cell polarity through coupling microtubules and nuclear lamina, emphasizing the impact of altered microtubule stability and nuclear mechanotransduction in polarity defects.
    DOI:  https://doi.org/10.1038/s42003-025-09229-8
  19. Cell Death Discov. 2025 Dec 11.
    The inhibition of de novo purine synthesis increases LAMP2 expression to preserve cell viability.
    Angela De Cristofaro, Serena Castelli, Federica Felice, Maria Rosa Ciriolo, Enrico Desideri.
      Cancer cells rewire their metabolism to sustain the high proliferative rate. Metabolism is therefore a common vulnerability of cancer cells, successfully exploited for therapeutic purposes. Intrinsic tumor characteristics and adaptive responses of cancer cells can however reduce the short and long-term efficacy of such a strategy. Understanding the determinants of therapy response and the mechanisms of chemoresistance is crucial to maximize therapy efficacy. In cancer, lysosomes undergo massive changes in their localization, size, and composition that support tumor progression. Additionally, lysosomes are one of the crucial drivers of chemoresistance via the drug sequestration or by facilitating adaptations to stress conditions. In the last decades, several reports have shown that lysosomal membrane proteins, such as the lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2), are deregulated in different cancer types and their expression has been correlated to drug efficacy. We performed an in silico gene essentiality and drug sensitivity screenings, revealing that LAMP2 expression is one of the determinants of resistance to inhibitors of de novo purine synthesis. In vitro experiments confirmed the in silico data and also showed that purine synthesis inhibitors trigger a ROS- and transcriptional-dependent increase of LAMP2. Our results identify the upregulation of LAMP2 expression as an adaptive response to purine synthesis inhibition to preserve cell viability and, in those tumors showing high LAMP2 levels, could also be an indicator of intrinsic resistance to these drugs that may be taken into consideration during the selection of the most appropriate therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02884-0
  20. FASEB J. 2025 Dec 15. 39(23): e71316
    CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.
    Xiaomei Liang, Yilu Zheng, Bangxue Jiang, Yuling Huang, Jing Tang, Haimei Deng, Chenxing Zhang, Minyi Zhao, Dongjun Lin.
      Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the malignant proliferation of myeloid progenitor cells. Although the introduction of the B-cell lymphoma-2 (BCL-2) inhibitor Venetoclax (VEN) has significantly improved patient outcomes and established it as a first-line treatment, high rates of drug resistance and relapse remain major clinical challenges. We integrated RUNX3 chromatin immunoprecipitation sequencing (ChIP-seq) data with the GAPIA2 database to identify CRTC2 as a key candidate gene. Subsequently, we employed qRT-PCR to compare CRTC2 expression levels between donors and AML patients. The role of CRTC2 in apoptosis was further validated through knockdown and overexpression experiments in various cell lines. To investigate the impact of CRTC2 on AML progression, we established a cell line-derived xenograft (CDX) model. The proportion of human CD45-positive (hCD45+) cells in the bone marrow and liver was assessed, and histological examination was conducted using HE staining, along with peripheral blood smear analysis. In addressing VEN resistance, we analyzed CRTC2 expression patterns in clinical samples and explored the synergistic therapeutic effect of a CRTC2 inhibitor in combination with VEN. To further elucidate the underlying molecular mechanisms, we performed mitochondrial function assays and analyzed mitochondrial translation-related proteins. Clinical analyses have demonstrated that elevated expression levels of CRTC2, a downstream target of RUNX3, are significantly correlated with poor prognosis in patients with AML. Functional experiments have shown that CRTC2 plays a role in disease progression by modulating apoptosis in AML cells. The knockdown of CRTC2 was observed to delay disease progression in CDX mouse models. Additional investigations revealed a positive correlation between CRTC2 expression and resistance to VEN in AML cells, with CRTC2 inhibition synergistically enhancing VEN's cytotoxic effects. Mechanistic studies suggest that increased mitochondrial activity contributes to VEN resistance, thereby identifying a potential molecular target for overcoming drug resistance. CRTC2 is a key regulator in AML, with high expression levels promoting disease progression and resistance to VEN. Inhibiting CRTC2 reduces mitochondrial translation and energy reserves, increasing AML cell sensitivity to VEN. These results highlight CRTC2 as a promising therapeutic target and suggest a new strategy to overcome VEN resistance.
    Keywords:  CRTC2; acute myeloid leukemia; drug resistance; mitochondrial translation
    DOI:  https://doi.org/10.1096/fj.202503054R
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