bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–05–24
sixteen papers selected by
William Grey, University of York
  1. Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype.
  2. Targeting ZMIZ1 induces differentiation in acute myeloid leukemia via chromatin remodeling.
  3. Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.
  4. Cord Blood Grafts for Relapsed/Refractory AML: Time for Prospective Studies.
  5. Stromal Gasdermin D-mediated Pyroptosis Drives Maladaptive CD4⁺ T-cell Remodeling in Tet2-Deficient Hematopoiesis.
  6. Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.
  7. Bridging Simplicity and Depth in Single-Cell Proteomics: A Cost-Effective Workflow and an Expanded Framework for Data Evaluation.
  8. Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress.
  9. Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.
  10. A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
  11. A unifying model of stem cell dynamics explains age-related methylation patterns across mammals.
  12. Redox regulation of EGFR activation by thioredoxin reductase 3 drives resistance to EGFR inhibitors in triple-negative breast cancer.
  13. Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.
  14. Biophysical principles of cell competition and elimination.
  15. Modeling human B cell development with pluripotent stem cells.
  16. Septin crosstalk with microtubules and actin is regulated by a GSK3-dependent phosphoswitch.
  1. Blood. 2026 May 21. pii: blood.2025031996. [Epub ahead of print]
    Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype.
    J Philip Creamer, Suhita Ray, Sintra Stewart, Suleyman Gulsuner, Antoine N Saliba, Jieya Wu, Frank Y Huang, Aino-Maija Leppä, Bofei Wang, Hussein A Abbas, Janis L Abkowitz, Jacob S Appelbaum, Scott H Kaufmann, Pamela S Becker, Andreas Trumpp, Vaidehi Jobanputra, Min Fang, Elizabeth M Swisher, Sergei Doulatov.
      Clonal acquisition of multiple chromosomal abnormalities in hematopoietic stem and progenitor cells (HSPCs) is a hallmark of high-risk acute myeloid leukemias with complex karyotype (AML-CK). AML-CK is associated with TP53 mutations and chromosome 5q deletions (del5q); however, the drivers and clonal trajectories of aneuploid evolution in HSPCs remain unknown. We have developed a patient-derived induced pluripotent stem cell (iPSC) model in which preleukemic HSPCs clonally evolve to distinct, highly aneuploid states following transient mitotic inhibition. By tracking chromosome evolution at single cell resolution, we show that TP53-mutant HSPCs with del5q, but not TP53- mutation alone, evolved complex chromosomal changes. Clonal evolution was marked by stepwise acquisition of numerical and structural chromosome changes seen in AML-CK patients, with individual abnormalities conferring fitness advantage. iPSC-derived aneuploid HSPCs and primary AML-CK patient samples exhibited a conserved gene expression signature marked by upregulation of PTEN, cohesins, and anti-apoptotic factor BCL2, indicative of a shared aneuploid cell state in HSPCs. Clinical BCL2 inhibitor venetoclax eradicated BCL2-dependent aneuploid clones, with resistant clones undergoing a lineage switch to upregulate alternative BCL2 factors. In summary, we demonstrate that mutant TP53 and del5q drive chromosome evolution marked by stepwise acquisition of individual abnormalities. Moreover, aneuploid HSPCs exhibit a shared gene expression state which confers unique targetable therapeutic vulnerabilities in AML-CK.
    DOI:  https://doi.org/10.1182/blood.2025031996
  2. Signal Transduct Target Ther. 2026 May 19. pii: 189. [Epub ahead of print]11(1):
    Targeting ZMIZ1 induces differentiation in acute myeloid leukemia via chromatin remodeling.
    Huimin Li, Yabin Liu, Jiachen Cui, Ziyu Fu, Yiyang Xu, Sizhe Yang, Kai Zhu, Yuhao Xue, Yi Zhang, Yiheng Zhao, Guiqiyang Xiang, Xiaoguang Xu, Fulun Jiao, Shuting Yu, Qiang Wang, Yuting Dai, Qianqian Zhang, Jianfeng Li, Ruihong Zhang, Fangyi Dong, Shanhe Yu, Shengyue Wang, Saijuan Chen, Bo Jiao, Shuo Chen, Yun Tan.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by profound transcriptional dysregulation and impaired hematopoietic differentiation. While differentiation therapy has revolutionized treatment in acute promyelocytic leukemia (APL), analogous strategies in non-APL AML remain elusive. Here, we identify ZMIZ1 (Zinc finger MIZ domain-containing protein 1) as a previously unrecognized transcriptional co-regulator that enforces differentiation blockade in AML from a targeted CRISPR-Cas9 screen. ZMIZ1 expression is elevated in AML patients and correlates with adverse outcomes. Genetic ablation of ZMIZ1 in leukemic cells induces terminal differentiation, reduces leukemia cell stemness, restores anti-leukemic immune responses, and significantly prolongs survival in murine AML models. Mechanistically, ZMIZ1 forms phase-separated nuclear condensates and maintains the super-enhancer architecture of genes critical for hematopoietic identity and immune evasion. Integrated Hi-C and ChIP-seq analyses reveal that ZMIZ1 cooperates with MEF2D (Myocyte-specific enhancer factor 2D) to promote enhancer-promoter looping and transcriptional output. Finally, we report the development of small-compounds potentially targeting ZMIZ1 with high binding affinity, selective on-target activity, and potent in vivo efficacy in both the murine AML model and AML organoids. Collectively, these findings uncover ZMIZ1 as a targetable epigenetic vulnerability in AML, underscoring its potential as a promising therapeutic target for differentiation-based treatment strategies.
    DOI:  https://doi.org/10.1038/s41392-026-02766-6
  3. Blood Cancer Discov. 2026 May 18.
    Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.
    Goichi Tatsumi, Rajni Kumari, Yutaro Suzuki, Shuting Li, Russell Scharf, Samuel J Taylor, Sriram Sundaravel, Amit Verma, Justin C Wheat, Ulrich Steidl.
      Chemotherapy resistance remains a critical challenge in the treatment of patients with cancer, including acute myeloid leukemia (AML). While genetic alterations can contribute to resistance, the role of rapid-adaptive non-genetic mechanisms, particularly transcription dynamics, remains poorly understood. Here, we demonstrated that short-term treatment of AML cells with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of a cell population with significant RNA induction and increased AraC resistance in cell lines and primary patient samples. Mechanistically, transcriptomic and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH revealed rapid induction of transcriptional dynamics and upregulation of key transcription factors (TFs) - which we term "AraC rapid response TFs". Functionally, short-term pre- and co-treatment with RNA transcription inhibitors suppressed chemotherapy-induced RNA induction and prevented resistance acquisition in vitro and in vivo. Furthermore, CRISPR-mediated suppression of TFs PU.1 and GATA1 significantly attenuated AraC resistance. Our findings reveal a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0317
  4. Transplant Cell Ther. 2026 May;pii: S2666-6367(26)00274-5. [Epub ahead of print]32(5): 515-517
    Cord Blood Grafts for Relapsed/Refractory AML: Time for Prospective Studies.
    Andromachi Scaradavou.
      
    Keywords:  AML; cord blood; leukemia; refractory; transplantation
    DOI:  https://doi.org/10.1016/j.jtct.2026.04.013
  5. bioRxiv. 2026 May 05. pii: 2026.05.01.722102. [Epub ahead of print]
    Stromal Gasdermin D-mediated Pyroptosis Drives Maladaptive CD4⁺ T-cell Remodeling in Tet2-Deficient Hematopoiesis.
    Kehan Ren, Xu Han, Ermin Li, Pan Wang, Honghao Bi, Wenjie Cai, Inci Aydemir, Ching Man Wai, Hongshen Niu, Jing Yang, Yijie Liu, Brian Vadasz, Madina Sukhanova, Deyu Fang, Weiguo Cui, Peng Ji.
      An inflammatory bone marrow microenvironment is increasingly recognized as critical in myeloid disease evolution, yet how stromal inflammation interfaces with adaptive immunity remains poorly defined. Here, we show that stromal pyroptosis drives mutation-specific myeloid expansion by coordinating monocytic remodeling and CD4⁺ T-cell activation. Genetic ablation of gasdermin D in the bone marrow stroma suppressed stromal pyroptosis and attenuated Tet2-deficient myeloid expansion. Tet2 deficiency skewed monocyte and macrophage differentiation toward an activated, antigen-presenting state that interacted with pyroptotic stromal cells to promote expansion of a distinct CD4⁺ T-cell population. These cells expressed canonical T follicular helper markers ( Bcl6 , Cxcr5 , Il21 , and Cd40l ) together with interferon-responsive and tissue-interaction programs, consistent with an inflammation-adapted T FH -like state. CD40L produced by these cells reinforced the expansion of Tet2-deficient monocytes and macrophages, establishing a feed-forward stromal-immune circuit. Disruption of this axis through stromal gasdermin D deficiency or CD40L blockade attenuated myeloid expansion in vivo. Consistent with these findings, patients with isolated TET2 loss-of-function mutations exhibited CD4⁺ T-cell skewing and CD40L + T-cell-rich tertiary lymphoid structures in the bone marrow. Together, these data identify a pyroptosis-dependent stromal-immune axis that links early myeloid inflammation to maladaptive remodeling of adaptive immunity and reveals a context-dependent therapeutic vulnerability in Tet2-deficient hematopoiesis.
    DOI:  https://doi.org/10.64898/2026.05.01.722102
  6. Oncogenesis. 2026 May 16.
    Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.
    Dominik A Nahotko, Brian Lee, Emely Lopez Fajardo, Aneta H Baran, Szymon K Filip, Peter A Faull, Elizabeth T Bartom, Masha Kocherginsky, Peng Gao, Jason Miska, Diana Saleiro, Elspeth M Beauchamp, Leonidas C Platanias.
      La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates translation of mRNAs containing a 5'-terminal oligopyrimidine motif. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and multi-omics analyses, we investigated LARP1's role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to 5-azacytidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR and CDK9. Proteomics analysis uncovered additional effects of LARP1 loss on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed reprogramming of arginine/creatine metabolism and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated across omics layers upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities in leukemia cells, not addressed by current therapies.
    DOI:  https://doi.org/10.1038/s41389-026-00623-3
  7. J Proteome Res. 2026 May 19.
    Bridging Simplicity and Depth in Single-Cell Proteomics: A Cost-Effective Workflow and an Expanded Framework for Data Evaluation.
    Shuxin Chi, Jason Rogalski, Huan Zhong, Esperanza Garcia Martinez, Arpa Ebrahimi, Rachel Wong, Melanie L Bailey, Marco A Marra, Claudia S Maier, Terrance P Snutch, Leonard J Foster.
      Single-cell proteomics (SCP) offers direct insight into functional protein states that drive cellular heterogeneity, complementing genomic and transcriptomic analyses. Although recent reports have demonstrated improved proteome coverage, their reliance on specialized instrumentation limits the broader adoption. Additionally, current evaluation practices remain largely centered on protein and peptide identification counts, which alone do not fully reflect data quality or biological interpretability. Here, we describe an accessible, label-free SCP workflow that implements easily accessible laboratory equipment: a single-cell dispenser, conventional multiwell plates, and an incubator with water-bath-based humidity control. Using trapped ion mobility spectrometry─time-of-flight mass spectrometry (timsTOF), we systematically optimized key sample preparation variables, including trypsin concentration, incubation time, reduction/alkylation, digestion conditions, and plate types, which together maximize data quality and reproducibility. We further introduce a data quality framework that moves beyond identification counts, emphasizing quantitative consistency and biological interpretability via individual protein coverage completeness across cells, coefficients of variation across technical replicates, peptide-to-protein ratios, and single-cell-to-bulk correlations. Collectively, our approach lowers technical barriers to accessing SCPs while enabling more rigorous, interpretable, and scalable SCP analysis across diverse research contexts.
    Keywords:  data visualization; liquid chromatography−mass spectrometry; sample preparation; single-cell proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.6c00046
  8. Sci Adv. 2026 May 22. 12(21): eadz7896
    Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress.
    Michael C Mazzola, Ting Zhao, Anna Kiem, Trine A Kristiansen, Karin Gustafsson, Lai Ping Wong, Emily Scott-Solomon, Marissa D Fahlberg, Christina Mayerhofer, Ernst Mayerhofer, Sarah Forward, Emane Rose Assita, Giulia Schiroli, Maris Handley, Youmna Kfoury, Tsuyoshi Fukushima, Dan Li, Samuel Keyes, Azeem Sharda, Jelena Milosevic, Hiroki Kato, Pavel Ivanov, David B Sykes, Sheldon J J Kwok, Ruslan I Sadreyev, Vijay G Sankaran, Ya-Chieh Hsu, David T Scadden.
      Cell stress can increase the use of methylated guanosine (m7G) cap-independent, internal ribosome entry site (IRES)-mediated translation initiation relative to cap-dependent translation (IRES/Cap). Reporters that quantify IRES/Cap have demonstrated differential activity across cultured cell types and stress conditions. By generating an IRES/Cap reporter mouse, we were able to systematically evaluate IRES/Cap across distinct tissues and cell types during physiological stresses and lineage commitment. Caloric stress invoked the expected boost in IRES/Cap translation regardless of differentiation state, but unexpectedly, IRES/Cap progressively increased during hematopoietic and epithelial (hair follicle) differentiation under normal, homeostatic conditions. This was independent of total protein output or cell cycle. Even within cells of a given differentiation state, cells with lower relative IRES utilization had markedly higher multipotent capability in vivo. The RNA processing protein PTBP1 is a mediator of this translation initiation preference. Therefore, low IRES/Cap is a signature of high stemness and suggests that modulation of translation initiation participates in cell differentiation state.
    DOI:  https://doi.org/10.1126/sciadv.adz7896
  9. Blood. 2026 May 18. pii: blood.2025030554. [Epub ahead of print]
    Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.
    Varun S Sudunagunta, Edna M Stewart, Yi Chen, Hongxia Yan, Sebastian Fernando, Viviana Scoca, John Pantazi, Rong Deng, Jane J Xu, Narla Mohandas, Aaron D Viny.
      The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains incompletely characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome (MDS) and myeloid leukemia of Down Syndrome, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility determines GATA1 cistrome specificity and lineage fate decisions. To understand the connection between chromatin accessibility and GATA1, we comprehensively studied erythropoiesis in Stag2∆ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid differentiation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Despite unchanged Gata1 expression, Gata1 occupancy was reprogrammed from erythroid to megakaryocyte targets with Fli1 motifs enriched at Stag2∆ Gata1 binding sites. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays, which was partially reversed with Fli1 knockdown. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study establishes chromatin accessibility as a determinant of transcription factor binding specificity, revealing an accessibility-driven Gata1 retargeting mechanism underlying MDS dyserythropoiesis.
    DOI:  https://doi.org/10.1182/blood.2025030554
  10. Blood Adv. 2026 May 20. pii: bloodadvances.2025019380. [Epub ahead of print]
    A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
    Nour Sabiha Naji, Taha Soueidatt Ahmedna, Xinghan Zeng, Yuju An, Yashvi Hemani, Brandy Perkins, Zanshé Thompson, Tushar D Nichakawade, Yanyan Wang, Bum Seok Lee, Evangeline Watson, Theodora Chatzilygeroudi, Li Z Luo, Bogdan Paun, Melanie Klausner, Teodora Diana Supeanu, Ivana Gojo, Gabriel Ghiaur, Amy E DeZern, Mark J Levis, Linda M S Resar, Richard J Jones, J David Peske, Styliani Karanika, Suman Paul, Theodoros Karantanos.
      Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019380
  11. Nat Aging. 2026 May 19.
    A unifying model of stem cell dynamics explains age-related methylation patterns across mammals.
    Samuel J C Crofts, Caleb M Grenko, Riccardo E Marioni, Eric Latorre-Crespo, Tamir Chandra.
      DNA methylation changes are reliable biomarkers of aging, but the driving mechanisms remain poorly understood. Here we present SCARLET (Stem Cells and Age-ReLated Epigenetic Trajectories), a parsimonious mathematical model that describes how methylation changes in blood arise and propagate through hematopoietic stem cell divisions. Using a large human cohort, we demonstrate that seemingly distinct age-related methylation patterns can be explained by a unifying mechanistic model. We show that SCARLET captures known drivers of epigenetic aging, with accelerated individuals showing reduced ratios of stem cell pool size to division rate (N/s). Applying SCARLET to methylation data from 11 mammalian species reveals that N/s scales with maximum lifespan, suggesting that evolutionary adjustments to stem cell dynamics, rather than epigenetic maintenance efficiency, drive the previously observed relationship between methylation rates and lifespan. Our findings provide a quantitative framework for understanding epigenetic aging and suggest that stem cell dynamics may be a key driver of aging across mammals.
    DOI:  https://doi.org/10.1038/s43587-026-01125-y
  12. Cell Death Discov. 2026 May 19.
    Redox regulation of EGFR activation by thioredoxin reductase 3 drives resistance to EGFR inhibitors in triple-negative breast cancer.
    Prahlad V Raninga, Göknur Giner, Sivanandhini Sankarasubramanian, Murugan Kalimutho, Marco J Herold, Antoine de Weck, Kum Kum Khanna.
      Although 40-70% of TNBC cases overexpress EGFR, clinical responses to EGFR-targeted therapies have been minimal. This poor efficacy may result from intrinsic resistance mechanisms, inactive EGFR signaling, or reduced EGFR localization on the plasma membrane. To identify genetic determinants of EGFR inhibitor resistance, we performed a genome-wide CRISPR/Cas9 knockout screen in MDA-MB-231 cells. The screen revealed that loss of the redox-regulating enzyme Thioredoxin Reductase 3 (TXNRD3) sensitized TNBC cells to the EGFR inhibitor erlotinib. Functional validation showed that both siRNA-induced knockdown and pharmacological inhibition of TXNRD3 with the FDA-approved drug auranofin significantly enhanced the cytotoxic effects of EGFR inhibitors in EGFR-high TNBC cells. Mechanistically, TXNRD3 depletion or inhibition increased intracellular reactive oxygen species (ROS), leading to oxidation-dependent activation and phosphorylation of EGFR (Y1068) and subsequent activation of downstream signaling pathways in TNBC cells that otherwise lack active EGFR. The combined treatment of auranofin and EGFR inhibitors triggered GSDME-mediated pyroptosis in a ROS-dependent manner. Importantly, the combination of auranofin with erlotinib exhibited potent anti-tumor efficacy in vivo in both MDA-MB-231 xenograft and 4T1.2 syngeneic TNBC models. Collectively, our findings identify TXNRD3 as a redox-dependent regulator of EGFR activity and drug response in TNBC and demonstrate that auranofin-mediated TXNRD3 inhibition can re-activate EGFR signaling, thereby sensitizing TNBC tumors to EGFR-targeted therapy. This study provides a mechanistic rationale for repurposing auranofin in combination with EGFR inhibitors as a novel therapeutic strategy for EGFR-high TNBCs.
    DOI:  https://doi.org/10.1038/s41420-026-03157-0
  13. Cell. 2026 May 15. pii: S0092-8674(26)00504-0. [Epub ahead of print]
    Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.
    Jeremy R Bjelajac, Adrià Cañellas-Socias, Preeti Nehra, Kevin Reynolds, Meena Malipatlolla, Naiara Martinez Velez, Diane C Manjarrez, Katie Ho, Peng Xu, Jennifer L Hamad, Sean A Yamada-Hunter, Louai Labanieh, Elena Sotillo, Crystal L Mackall.
      We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation-termed activation-induced release (AIR). Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency. In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation. AIR's modularity supports higher-order logic-gating; AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR. Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions. AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies.
    Keywords:  ADAM17; CAR; T cells; bioengineering; cancer; immunotherapy; protease; synthetic biology
    DOI:  https://doi.org/10.1016/j.cell.2026.04.037
  14. Trends Cell Biol. 2026 May 18. pii: S0962-8924(26)00067-X. [Epub ahead of print]
    Biophysical principles of cell competition and elimination.
    Andreas Schoenit, René-Marc Mège, Benoît Ladoux.
      Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.
    Keywords:  cell competition; cell extrusion; epithelia; force transmission; tissue mechanics
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.009
  15. bioRxiv. 2026 May 07. pii: 2026.05.04.722674. [Epub ahead of print]
    Modeling human B cell development with pluripotent stem cells.
    Xiaoning Sun, Jamie J Kwan, Krishna Kothari, Alexandra F Nazzari, Astrid Kosters, Colin A Fields, Bao Q Thai, Deepta Bhattacharya, Michael Atkins, Kelvin Chan Tung, Xinyuan Zhao, Vladimir T Manchev, Marion Kennedy, Eliver Ghosn, Gordon Keller.
      The ability to generate functional B cells from human pluripotent stem cells (hPSCs) would open new opportunities to develop novel B cell-based therapies to treat a range of human diseases and disorders. Towards this goal, we established a protocol that promotes the efficient development of B lineage cells from definitive hematopoietic progenitors generated from different hPSC lines. Flow cytometric and multi-omic scRNA-seq analyses revealed that B cell development from hPSCs transitions through the well-established pro-B, pre-B and naïve B cell stages, accurately recapitulating B lymphopoiesis in the human adult bone marrow. Importantly, the naïve B cells generated with this approach could be induced to mature into plasma cells that secrete antibodies and undergo class switching. Analyses of signaling pathways that regulate B lymphopoiesis in these cultures uncovered a potent inhibitory effect of IL-7 on functional IgH rearrangement, resulting in the development of abnormal cells that failed to undergo pre-B cell maturation. Finally, analysis of the different hPSC-derived hematopoietic programs revealed that both definitive and yolk sac progenitors display B cell potential, indicating that there are distinct developmental sources of human B lineage cells. Taken together, these findings demonstrate the efficient generation of B cells from hPSCs and, in doing so, provide a system for further investigating the earliest stages of human B lymphopoiesis and a source of appropriately staged plasma cells for future therapeutic applications.
    DOI:  https://doi.org/10.64898/2026.05.04.722674
  16. bioRxiv. 2026 May 09. pii: 2026.05.06.723191. [Epub ahead of print]
    Septin crosstalk with microtubules and actin is regulated by a GSK3-dependent phosphoswitch.
    Md Noor A Alam, TrishaJean C Holt, Andrew W Schaefer, Franklin Mayca-Pozo, Sarath Reghunathan, Sarah M Butts, Priyanka Bhakt, Ilona A Kesisova, Elias T Spiliotis.
      Septins are cytoskeletal filaments that associate with the actin and microtubule cytoskeleton, but the mechanisms that govern septin crosstalk and function with these networks are largely unknown. Here, we show that glycogen synthase kinase 3 (GSK3) directly phosphorylates septin-9 (SEPT9), acting as a molecular switch that bidirectionally controls septin distribution between actin and microtubules. We show that GSK3 inhibition redistributes endogenous SEPT9 toward microtubules in multiple cell types. Phosphomimetic mutations at serines 82 and 85 reduce microtubule binding and enhance actin association in cells and in vitro, while phosphonull mutations promote microtubule binding and growth. In primary hippocampal neurons, GSK3β inactivation promotes SEPT9-microtubule association, and phosphomimetic mutations impair asymmetric neurite growth during neuronal polarization. These findings reveal a phosphorylation-dependent mechanism of septin partitioning between actin and microtubules, placing the cytoskeletal functions of septins under the control of GSK3 - a kinase linked to multiple signaling pathways of cell physiology and metabolism.
    Highlights: GSK3β phosphorylates SEPT9, and its activity gates septin-cytoskeleton associationS82/S85 phosphorylation reduce microtubule binding and increase actin localizationUnphosphorylated SEPT9 binds preferentially to microtubules, promoting their growthGSK3β inactivation drives SEPT9 to microtubules to establish neuronal polarity.
    DOI:  https://doi.org/10.64898/2026.05.06.723191
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