bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–02–01
nineteen papers selected by
William Grey, University of York
  1. A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
  2. High-Dimensional Spatiotemporal Single-Cell Atlas and 3D imaging of Bone Marrow Microenvironment during CML Progression.
  3. Single cell transcriptomics derived combinatorial markers distinguished leukemic stem cells from hematopoietic stem cells in acute myeloid leukemia.
  4. Transduction of Quiescent Human Hematopoietic Stem and Progenitor Cells Using Lentiviral Vectors and Virus-Like Particles.
  5. Crip2 preserves hematopoietic stem and progenitor cell production through inhibition of Notch signals.
  6. Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.
  7. Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.
  8. The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia.
  9. Epigenetic silencing and pharmacological inhibition of EIF5A2 foster venetoclax sensitivity in acute myeloid leukaemia.
  10. GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.
  11. GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
  12. "Next-Generation Cord Blood Expansion: Bridging the Cell Dose Gap with Bioengineered Niches and Clinical Breakthroughs".
  13. Aged murine bone marrow myeloid and mesenchymal cells develop unique senescence phenotypes.
  14. Fucosylation enhances CD34⁺ hematopoietic stem cell homing and longevity via E-selectin-mediated adhesion and signaling.
  15. Phenylhydrazone-based endoplasmic reticulum proteostasis regulator compounds with enhanced biological activity.
  16. Comparison of changes in blood cells and hemostatic biomarkers in mouse xenograft models of acute myeloid leukemia and acute promyelocytic leukemia.
  17. Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress.
  18. Pan-cancer N-glycoproteomic atlas of patient-derived xenografts uncovers FAT2 as an actionable surface target.
  19. Mitochondria as sources and targets of cellular signaling.
  1. Aging Cell. 2026 Feb;25(2): e70394
    A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
    Ryan R White, Kun Xiong, Matthew Wakai, Allison Surian, Christina Adler, Nicole Negron, Min Ni, Tea Shavlakadze, Yu Bai, David J Glass.
      Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.
    DOI:  https://doi.org/10.1111/acel.70394
  2. Blood. 2026 Jan 27. pii: blood.2025029824. [Epub ahead of print]
    High-Dimensional Spatiotemporal Single-Cell Atlas and 3D imaging of Bone Marrow Microenvironment during CML Progression.
    Lanzhu Li, Isabelle Rottmann, Borhan R Saeed, Geoff Ivison, Huan Wei, Jan Christian Schroeder, Gina Dunkel, Karen Greif, Yizheng Zhang, Ahmad Makky, Adrian Franz Ochsenbein, Carsten Riether, Yury Goltsev, Garry Nolan, Aaron T Mayer, Bettina Weigelin, Christian M Schürch.
      The bone marrow microenvironment (BMME) is essential for hematopoiesis and immunity, yet spatiotemporal single-cell analysis during leukemogenesis remains challenging. We characterized the BMME in femurs from wild-type and chronic myeloid leukemia (CML) mice at 7, 14 and 21 days post-induction by highly multiplexed and 3D microscopy. Using a 54-marker CODEX panel, we profiled 2,033,725 cells in 55 regions of interest and identified 41 cell-types. During CML progression, we observed myeloid and progenitor cell expansion, increased PD-L1+ leukemic cells, PD-1 upregulation on CD4+ and CD8+ T-cells, and a profound loss of B-cells, plasma cells and bone cells. Advanced CML exhibited a striking expansion of immature, pericyte-deficient vasculature that disrupted vascular niches and impaired hematopoietic stem/progenitor cell positioning. Spatial mapping revealed leukemia-specific cellular neighborhoods enriched in PD-1+CD8+ T-cells, suggesting localized immune exhaustion. Early CML showed increased contacts between plasmacytoid dendritic cells and megakaryocytes, whereas advanced CML featured heightened megakaryocyte emperipolesis of non-leukemic granulocytes. Megakaryocytes were morphologically irregular in CML mice and patient BM biopsies. In contrast, in mice with acute myeloid leukemia, vasculature and megakaryocytes were reduced, while remaining megakaryocytes retained normal morphology. Laser-capture microdissected megakaryocytes from newly diagnosed CML patients had reduced cytoskeleton gene expression, which was reversed in advanced cases treated with tyrosine kinase inhibitors. 3D imaging revealed vascular disorganization and depleted megakaryocytes in the diaphysis, underscoring region-specific pathology. Together, this study provides a spatiotemporal single-cell atlas of the BMME during leukemic progression, showing how leukemic cells reprogram it to support their expansion and immune evasion.
    DOI:  https://doi.org/10.1182/blood.2025029824
  3. Leuk Res. 2026 Jan 21. pii: S0145-2126(26)00014-7. [Epub ahead of print]161 108170
    Single cell transcriptomics derived combinatorial markers distinguished leukemic stem cells from hematopoietic stem cells in acute myeloid leukemia.
    Aafreen Khan, Smeeta Gajendra, Vivek Kumar Singh, Deepshi Thakral, Sameer Bakhshi, Ranjit Kumar Sahoo, Rachna Seth, Sandeep Rai, Ritu Gupta.
      Leukemic stem cells (LSCs) play a critical role in relapse and chemoresistance in acute myeloid leukemia (AML). These LSCs originate from Hematopoietic stem cells (HSCs) after acquiring genetic and molecular aberrations. Both HSCs and LSCs predominantly reside in CD34 +CD38- fraction of the bone marrow and their phenotypic similarities poses a challenge in distinguishing between them. In addition, the phenotypic heterogeneity of LSCs limits the precise quantitation of this population in clinical studies. Delineation of LSCs from HSCs and quantification of LSC burden is crucial as it is correlated with survival rates and treatment outcomes in AML. In this study, we employed single cell transcriptomic analysis to identify differentially expressed cell surface markers that can discriminate LSCs from HSCs. Our data revealed several candidate markers, including CD48, CD52, CD96 and CD88 with distinct expression patterns in LSCs compared to HSCs. We further validated the expression levels of these markers as potential biomarkers for the identification of LSCs in both CD34 + and CD34- AML. Among these cell surface markers, CD52, CD96 and CD48 were significantly over-expressed in LSCs relative to HSCs. Incorporating these markers in combination with established aberrant markers can enhance the identification of LSCs and help distinguish them from HSCs in both CD34 + and CD34- AML. Our findings support the use of an expanded combinatorial marker panel and warrants its further evaluation in a larger AML cohort, particularly in the context of measurable residual disease (MRD) assessment, prognostication and correlation with treatment response and survival outcomes.
    Keywords:  Acute Myeloid Leukemia; Flow Cytometry; HSC; LSC; Single cell transcriptome; Surface markers
    DOI:  https://doi.org/10.1016/j.leukres.2026.108170
  4. Curr Protoc. 2026 Jan;6(1): e70301
    Transduction of Quiescent Human Hematopoietic Stem and Progenitor Cells Using Lentiviral Vectors and Virus-Like Particles.
    Denise Klatt, Christian Brendel.
      Traditional retroviral gene transfer protocols for the genetic modification of hematopoietic stem and progenitor cells (HSPC) include a multiday ex vivo culture period, which can negatively affect the biology of the cells and is costly. As an alternative approach, we outline here a method for gene transfer into quiescent human HSPCs using lentiviral (LV) vectors and gamma-retroviral virus-like particles (eVLP). To achieve this, we use LV vectors and eVLPs pseudotyped with the modified baboon endogenous retroviral glycoprotein BaEVRLess, which targets the neutral amino acid transporters ASCT1 and ASCT2 on HSPCs. This envelope enables immediate transduction of freshly isolated or thawed, unstimulated HSPCs with higher gene transfer efficiencies than those obtained with VSVg-pseudotyped LV vectors and enables the transplantation of transduced HSPCs within less than 24 hr of cell isolation. These protocols provide detailed guidance on the production and titration of BaEVRLess-pseudotyped LV vectors and eVLPs and the cultivation and transduction of quiescent HSPCs, and highlights critical steps and potential pitfalls of these processes. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Generation of BaEVRLess-pseudotyped lentiviral vectors Alternate Protocol: Generation of BaEVRLess-pseudotyped virus-like particles Support Protocol: Preparation and testing of polyethyleneimine solution for DNA transfection Basic Protocol 2: Transduction of quiescent human CD34+ hematopoietic stem and progenitor cells.
    Keywords:  baboon endogenous retroviral glycoprotein; gene therapy; hematopoietic stem and progenitor cells (HSPCs); lentiviral vector; virus‐like particle
    DOI:  https://doi.org/10.1002/cpz1.70301
  5. Development. 2026 Jan 28. pii: dev.204359. [Epub ahead of print]
    Crip2 preserves hematopoietic stem and progenitor cell production through inhibition of Notch signals.
    Angelika G Aleman, Bianca Ulloa, Rigolin Nayak, Caitlin Ford, Kathryn S Potts, Carmen de Sena-Tomás, Camila Vicioso, Uday Rangaswamy, Harold K Elias, Michael G Kharas, Remo Sanges, Teresa Bowman, Kimara L Targoff.
      Hematopoietic stem and progenitor cells (HSPCs) have multilineage potential and sustain long-term self-renewal. Deriving patient-specific HSPCs has immense therapeutic potential to overcome the shortage of compatible donors for transplantation. In zebrafish, hemogenic endothelium (HE) is a specialized collection of dorsal aortic endothelial cells (ECs) that give rise to HSPCs. Our data reveal cysteine rich intestinal protein 2 (crip2) has a previously unrecognized function in establishing the proper EC environment for HSPC specification. To investigate the requirement of crip2, we generated loss-of-function alleles in crip2 and crip3, a gene family member with cardiovascular expression. crip2-/-;crip3-/- (cripDM) embryos exhibit decreased HSPC emergence with impaired lineage derivative production. Single cell RNA-sequencing of kdrl:mCherry+ ECs reveals upregulation of vascular development signature and failure to repress Notch signals during the vital transition of HE specification to HSPC emergence. Moreover, our data underscore that inhibition of Notch promotes HSPC generation in cripDM embryos and Crip genes operate through NF-κB to limit Notch. Identification of Crip2 as a novel regulator of Notch repression in HE will enhance our understanding of cues necessary to improve human HSPC production in vitro.
    Keywords:  Crip2; HSPC; Hemogenic endothelium; Notch; Zebrafish
    DOI:  https://doi.org/10.1242/dev.204359
  6. Blood Adv. 2026 Jan 29. pii: bloodadvances.2025018369. [Epub ahead of print]
    Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.
    Jeremy T Baeten, Sumedha Agashe, Imene Tabet, Jack T Wooldridge, Amber Carter, Jamie N Butler, Christopher A Miller, Nichole M Helton, Annabel Quinet, Kimberly B Johansson, Yichan Yang, Geoffrey L Uy, Alessandro Vindigni, Daniel C Link.
      TP53 mutations are found in 10-15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents, such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to hypomethylating agents in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ATR pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNMT1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATR inhibition and decitabine showing promise as a new therapeutic approach for TP53-MN.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018369
  7. Blood. 2026 Jan 29. pii: blood.2025030055. [Epub ahead of print]
    Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage.
    Steven Ngo, Giuseppe Alessandro D'Agostino, Despoina Papazoglou, Fatihah Mohamad Nor, Katja Finsterbusch, Khadidja Habel, Alessandra Ferrelli, Fernando Anjos-Afonso, Dominique Bonnet.
      The Bcl2 inhibitor venetoclax in combination with the hypomethylating agents azacitidine (ven/aza) has become increasingly utilized clinically for the treatment of many hematological malignancies. Whilst its effects on malignant cells have been extensively studied, its impact to the surrounding bone marrow microenvironment (BME) remains unexplored. In this study, we report that ven/aza therapy causes significant damage to the BME of mice. Comparatively high Bcl2 expression in the sinusoidal endothelial cell compartment (SEC) amongst all stromal subtypes, results in high sensitivity to ven/aza treatment, causing selective depletion of SECs and breakdown in cell-cell communication pathways in the endothelial cell (EC) network, leading to vascular leakiness in the BM. Furthermore, our detailed transcriptomic and imaging studies reveals significant downregulation of essential adhesion molecules in residual SECs, leading to significant defects in human hematopoietic stem/progenitor cell (HSPC) homing and engraftment of hematopoietic stem cells (HSCs) after ven/aza treatment. To conclude, our study showcases that maintaining SEC integrity in response to ven/aza therapy may play a key factor in achieving effective engraftment of donor derived HSCs.
    DOI:  https://doi.org/10.1182/blood.2025030055
  8. Blood Neoplasia. 2026 Feb;3(1): 100186
    The LMO2-LDB1-TAL1 complex regulates transcription networks in acute myeloid leukemia.
    Nicholas Dunham, Zhenjia Wang, Yaseswini Neelamraju, Yan Guo, B Bishal Paudel, Cem Meydan, Jorge A Gandara, Fady A Abdelmalak, Hao Fan, Joyce Hardwick, Justin H Layer, Tak Lee, Bernhard Maier, W Hayes McDonald, Isaani Patnaik, Subhash Prajapati, Franck Rapaport, Caroline Sheridan, Gloria Sheynkman, Paul Zumbo, Michael W Becker, Lars Bullinger, Martin P Carroll, Richard J D'Andrea, Richard Dillon, Ross L Levine, Christopher E Mason, Ari M Melnick, Donna S Neuberg, Stefan Bekiranov, Chongzhi Zang, Utpal P Davé, Francine E Garrett-Bakelman.
      Relapsed acute myeloid leukemia (relAML) remains a clinical challenge. We have shown that epigenetic heterogeneity may contribute to transcriptional dysregulation and disease progression in AML, but the specific aberrant transcriptional programs have not been identified. We analyzed molecular profiles from patient-matched diagnostic and relapse AML specimens. A subset of differentially expressed genes (DEG) that were disparate in direction of expression change identified 2 patient subtypes. We predicted that transcriptional regulators (TR) might regulate the expression patterns observed. The expression patterns of the top TR predicted for the disparate genes associated with clinical outcomes. The top TR predicted for the disparate DEG and DEG identified in a patient-derived xenograft model of relAML included members of the LIM domain only 2 - LIM domain binding 1 - TAL BHLH TF1, erythroid differentiation factor (LMO2-LDB1-TAL1) multisubunit complex (LTMC). Analysis of DepMap data identified LMO2-dependent cells with a subset highly expressing TAL1, suggesting coordinated regulation. TAL1 copurified in immunoprecipitation for LMO2 and LDB1 followed by tandem mass spectrometry analysis in HEL and K562 cells, and results from chromatin immunoprecipitation experiments suggest significant co-occupancy of TAL1 and LDB1. Loss-of-function experiments targeting LMO2, LDB1, and TAL1 in AML cell lines associated with reduced cell growth, downregulation of cell cycle genes, and a negative association with gene expression patterns observed in relapsed patients with increased TAL1 expression. Our results from primary AML specimens and functional analyses of AML cell lines supports an essential role for the LTMC in AML. Targeting the complex or downstream effectors could provide novel therapeutic considerations for a subset of patients with AML.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100186
  9. Br J Haematol. 2026 Jan 28.
    Epigenetic silencing and pharmacological inhibition of EIF5A2 foster venetoclax sensitivity in acute myeloid leukaemia.
    Eva Crespo-García, Carlos Quero-Dotor, Aleix Noguera-Castells, Laia Sancho-Vila, Laura Martinez-Verbo, Manel Esteller.
      We show how the loss of activity of the translation initiation factor EIF5A2-either through gene hypermethylation or pharmacologic inhibition of its highly specific hypusine post-translational modification-induces venetoclax sensitivity in acute myeloid leukaemia (AML) cells.
    Keywords:  DNA methylation; Epigenetics; acute myeloid leukemia; venetoclax
    DOI:  https://doi.org/10.1111/bjh.70339
  10. Blood. 2026 Jan 26. pii: blood.2025030464. [Epub ahead of print]
    GATA1 N-terminus coordinates metabolic reprogramming in erythropoiesis.
    Te Ling, Lavanya Bezavada, Rashid Mehmood, Kevin Zhang, Anitria Cotton, Jeremy Chase Crawford, Hongjian Jin, Surbhi Sona, Lei Li, Yan Ju, Lei Han, Nana Liu, Tam Tran, Hieu Vu, Yan Jin, Jinbin Zhai, Shondra M Pruett-Miller, Senthil Velan Bhoopalan, Jian Xu, Min Ni, John D Crispino.
      Mutations in GATA1 that cause skipping of exon 2, which encodes the N-terminus, are associated with the myeloid leukemia of Down syndrome and Diamond-Blackfan anemia (DBA). To elucidate the molecular function of this N-terminal region, we employed single-cell RNA sequencing (scRNA-seq) on fetal liver cells from Gata1 mutant embryos that express only the short isoform of GATA1 (GATA1s) lacking the N-terminus of full-length GATA1 (GATA1FL). scRNA-seq revealed defects in erythropoiesis and aberrant upregulation of glycolytic genes, including PKM, which encodes pyruvate kinase to catalyze the final and irreversible step of glycolysis. Using precision nuclear run-on sequencing (PRO-seq) and cleavage under targets and release using nuclease (CUT&RUN) following acute GATA1 deletion in erythroid cells, we identified PKM as a direct target of GATA1. Substitution of GATA1FL with GATA1s induced histone lactylation at the PKM promoter, increased PKM expression and activity, and enhanced glycolytic flux in erythroid progenitors, without affecting mitochondrial respiration. Importantly, PKM expression is also significantly elevated in DBA patients with RPS19 mutations, which is associated with reduced levels of GATA1, further supporting a link between GATA1s-driven defective erythropoiesis and dysregulated glycolysis. Together, these findings reveal that GATA1 controls not only heme metabolism, but also glycolytic reprogramming.
    DOI:  https://doi.org/10.1182/blood.2025030464
  11. Nature. 2026 Jan 28.
    GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
    Peiyuan Chai, Sina Kheiri, Andrew Kuo, Jessica Shah, Lauren Kageler, Ruiqi Ge, Jonathan Perr, Jennifer Porat, Charlotta G Lebedenko, Joao M L Dias, Eliza Yankova, Sandeep K Rai, Christopher P Watkins, Petar Hristov, Konstantinos Tzelepis, Timothy Hla, Ritu Raman, Eliezer Calo, Jeffrey D Esko, Ryan A Flynn.
      Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface-particularly in the context of cell surface RNA-remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4-8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A.
    DOI:  https://doi.org/10.1038/s41586-025-10052-8
  12. Stem Cell Rev Rep. 2026 Jan 29.
    "Next-Generation Cord Blood Expansion: Bridging the Cell Dose Gap with Bioengineered Niches and Clinical Breakthroughs".
    Ke Pi, Hamed Soleimani Samarkhazan, Farzaneh Tavakoli, Masoumeh Nouri, Nazli Servatian.
      
    Keywords:  Clinical translation; Cord blood expansion; Ex vivo culture; Hematopoietic stem cells; Regenerative niche engineering
    DOI:  https://doi.org/10.1007/s12015-026-11065-0
  13. J Clin Invest. 2026 Jan 27. pii: e195772. [Epub ahead of print]
    Aged murine bone marrow myeloid and mesenchymal cells develop unique senescence phenotypes.
    Madison L Doolittle, Mitchell N Froemming, Jennifer L Rowsey, Ming Ruan, Leena Sapra, Joshua N Farr, David G Monroe, Sundeep Khosla.
      Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or "senotype", is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast to clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice only had minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time period. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.
    Keywords:  Aging; Bone biology; Cellular senescence
    DOI:  https://doi.org/10.1172/JCI195772
  14. BMC Cancer. 2026 Jan 29.
    Fucosylation enhances CD34⁺ hematopoietic stem cell homing and longevity via E-selectin-mediated adhesion and signaling.
    Asma S Al-Amoodi, Arwa A Alghuneim, Jana S Malki, Shuho Nozue, Yanyan Li, Jing Kai, Huoming Zhang, Dalila Bensaddek, Amal Kamal Abdel-Aziz, Satoshi Habuchi, Jasmeen S Merzaban.
       BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a cornerstone treatment for blood disorders and hematological malignancies, although its efficacy is limited by inefficient stem cell homing to the bone marrow. We previously demonstrated that fucosylated HSC ligands interact with endothelial E-selectin to facilitate homing. However, the downstream consequences of modulating fucosylation in HSCs remain unclear. Here, we systematically characterized how enhancing or inhibiting fucosylation-via recombinant human fucosyltransferase 6 (FTVI) or 2-fluoro-L-fucose (2FF), respectively-affects migration, signaling, and engraftment of human granulocyte-colony stimulating factor-mobilized peripheral blood CD34⁺ (mPB-CD34⁺) cells.
    METHODS: Live-cell imaging under flow, phosphoproteomics, and transcriptomics were used to characterize rolling dynamics and intracellular signaling, and in vivo homing was assessed in immunodeficient xenograft mouse models.
    RESULTS: Fucosylation enhanced tether and sling formation, improved E-selectin binding, and increased homing to the bone marrow and spleen. FTVI-treated cells activated MAPK and PI3K/AKT/mTOR pathways and showed enriched Rho-GTPase signaling, associated with proliferation and migration. In contrast, 2FF-treated cells had impaired migration and reduced rolling efficiency. Long-term xenograft studies showed enhanced bone marrow engraftment/persistence of fucosylated cells without altering lineage output.
    CONCLUSION: Fucosylation critically modulates E-selectin interactions, migration, and intracellular signaling in HSCs. These findings highlight glycoengineering as a promising strategy to enhance HSC transplantation outcomes in cancer therapy.
    Keywords:  E-selectin; Fucosylation ; HSC migration; HSCT; MAPK; PI3K/AKT/mTOR; Rho-GTPase; Sialyl Lewis X; Translational glycobiology; glycoengineering
    DOI:  https://doi.org/10.1186/s12885-026-15614-1
  15. Elife. 2026 Jan 26. pii: RP107000. [Epub ahead of print]14
    Phenylhydrazone-based endoplasmic reticulum proteostasis regulator compounds with enhanced biological activity.
    Gabriel M Kline, Lisa Boinon, Adrian Guerrero, Sergei Kutseikin, Gabrielle Cruz, Marnie P Williams, Ryan J Paxman, William E Balch, Jeffery W Kelly, Tingwei Mu, R Luke Wiseman.
      Pharmacological enhancement of endoplasmic reticulum (ER) proteostasis is an attractive strategy to mitigate pathology linked to etiologically diverse protein misfolding diseases. However, despite this promise, few compounds have been identified that enhance ER proteostasis through defined mechanisms of action. We previously identified the phenylhydrazone-based compound AA263 as a molecule that promotes adaptive ER proteostasis remodeling through mechanisms including preferential activation of the ATF6 signaling arm of the unfolded protein response (Plate et al., 2016). However, the protein target(s) of AA263 and the potential for further development of this class of ER proteostasis regulators had not been previously explored. Here, we employ chemical proteomics to demonstrate that AA263 covalently targets a subset of ER protein disulfide isomerases, revealing a potential molecular mechanism for the activation of ATF6 afforded by this compound. We then use medicinal chemistry to establish next-generation AA263 analogs showing improved potency and efficacy for ATF6 activation, as compared to the parent compound. Finally, we show that treatment with these AA263 analogs enhances secretory pathway proteostasis to correct the pathologic protein misfolding and trafficking of both a destabilized, disease-associated α1-antitrypsin (A1AT) variant and an epilepsy-associated GABAA receptor variant. These results establish AA263 analogs with enhanced potential for correcting imbalanced ER proteostasis associated with etiologically diverse protein misfolding disorders.
    Keywords:  ATF6; biochemistry; chemical biology; endoplasmic reticulum; human; mouse; protein homeostasis; small molecule; unfolded protein response
    DOI:  https://doi.org/10.7554/eLife.107000
  16. Res Pract Thromb Haemost. 2026 Jan;10(1): 103319
    Comparison of changes in blood cells and hemostatic biomarkers in mouse xenograft models of acute myeloid leukemia and acute promyelocytic leukemia.
    Sierra J Archibald, Ana T A Sachetto, Xingru Zhu, Radhika Gangaraju, Nigel Mackman, Yohei Hisada.
       Background: Leukemia patients have an increased risk of both thrombosis and bleeding due to a dysregulated hemostatic system. Levels of coagulation and fibrinolysis activation markers are increased, whereas levels of platelets and fibrinogen are decreased in leukemia patients. Mouse models can be used to study the pathways that contribute to coagulopathy in leukemia.
    Objectives: To measure blood cells and hemostatic biomarkers in a mouse xenograft model of acute myeloid leukemia (AML) and compare them with a mouse xenograft model of acute promyelocytic leukemia (APL).
    Methods: We established a mouse xenograft model of AML by injecting HL-60-Luc2 cells into NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice and monitored the growth of leukemic cells by measuring luciferase expression. Levels of blood cells and hemostatic biomarkers were measured in leukemic mice. The parameters of the AML model were compared with those of the APL model using NB4-Luc cells.
    Results: AML mice exhibited an increase in white blood cells, an increase in a marker of coagulation activation (thrombin-antithrombin complexes), an increase in a marker of fibrinolysis activation (plasmin-antiplasmin complexes), and a decrease in platelets and fibrinogen compared with control mice. No increase in white blood cell counts was observed in APL mice. APL mice had significantly higher levels of thrombin-antithrombin complexes compared with AML mice.
    Conclusion: These leukemia mouse models can be used to understand how the hemostatic system is dysregulated in leukemia.
    Keywords:  coagulation; fibrinogen; fibrinolysis; leukemia; platelet
    DOI:  https://doi.org/10.1016/j.rpth.2025.103319
  17. EMBO Rep. 2026 Jan 27.
    Sec61β maintains cytoplasmic proteostasis via ARIH1-mediated translational repression upon ER stress.
    Hisae Kadowaki, Tomohisa Hatta, Kazuma Sugiyama, Tomohiro Fukaya, Takao Fujisawa, Takashi Hamano, Naoya Murao, Yasunari Takami, Shuya Mitoma, Tohru Natsume, Katsuaki Sato, Hiromi Hirata, Tamayo Uechi, Hideki Nishitoh.
      Disrupted proteostasis causes various degenerative diseases, and organelle homeostasis is therefore maintained by elaborate mechanisms. Endoplasmic reticulum (ER) stress-induced preemptive quality control (ERpQC) counteracts stress by reducing ER load through inhibiting the translocation of newly synthesized proteins into the ER for their rapid degradation in the cytoplasm. Here, we show that Sec61β, a translocon component, prevents the overproduction of ERpQC substrates, allowing for their efficient degradation by the proteasome. Sec61β inhibits the binding of translation initiation factor eIF4E to the mRNA 5' cap structure by recruiting E3 ligase ARIH1 and eIF4E-homologous protein 4EHP, resulting in selective translational repression of ERpQC substrates. Sec61β deficiency causes overproduction of ERpQC substrates and reduces proteasome activity, leading to cytoplasmic aggresome formation. We also show that Sec61β deficiency causes motor dysfunction in zebrafish, which is restored by exogenous ARIH1 expression. Collectively, translational repression of ERpQC substrates by the Sec61β-ARIH1 complex contributes to maintain ER and cytoplasmic proteostasis.
    Keywords:  ER Stress; ERpQC; Proteostasis; Translational Regulation
    DOI:  https://doi.org/10.1038/s44319-026-00690-y
  18. Cell Rep Med. 2026 Jan 23. pii: S2666-3791(25)00651-2. [Epub ahead of print] 102578
    Pan-cancer N-glycoproteomic atlas of patient-derived xenografts uncovers FAT2 as an actionable surface target.
    Meinusha Govindarajan, Salvador Mejia-Guerrero, Shawn C Chafe, Shahbaz Khan, Wei Shi, Matthew Waas, Martin A Rossotti, Amanda Khoo, Lydia Y Liu, Vladimir Ignatchenko, Simona Principe, Lusia Sepiashvili, Greg Hussack, Nazanin Tatari, Chitra Venugopal, Petar Miletic, Maxwell Topley, Shan Grewal, Dillon McKenna, Lucas C Asselstine, Maria-Jose Sandi, Nhu-An Pham, Alison Casey, Hyeyeon Kim, Christina Karamboulas, Jalna Meens, Peter Bergqvist, Begonia Silva, Patrick Chan, Liza Cerna-Portillo, Jasmine Chin, Abilasha Rao-Bhatia, Ming-Sound Tsao, Rama Khokha, Susie Su, Wei Xu, David Goldstein, Laurie Ailles, Vuk Stambolic, Fei-Fei Liu, Emma Cummins, Ismael Samudio, Sheila K Singh, Thomas Kislinger.
      Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central roles in cellular signaling, yet their promise remains largely untapped due to technical challenges inherent to profiling them. Here, we employ N-glycoproteomics to analyze 85 patient-derived xenografts (PDXs), constructing Glyco PDXplorer-an in vivo pan-cancer atlas of cancer-derived surface proteins. We develop a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validate FAT2 as a squamous-cancer-enriched surface protein minimally detected in normal tissue. Functional studies reveal that FAT2 is essential for head and neck squamous cancer (HNSC) cell growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR)-T cells targeting FAT2 demonstrate anti-tumor activity. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal platform to inform therapeutic target discovery across cancers.
    Keywords:  CAR-T; FAT2; N-glycoproteomics; head and neck squamous cancer; immunotherapy; pan-cancer atlas; patient-derived xenografts; squamous cell cancer; surfaceome; targeted therapy
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102578
  19. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
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