bims-scepro 2026-02-15 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–02–15
eighteen papers selected by
William Grey, University of York

Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging.
Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
Tissue-scale mapping reveals a central role of hepatoblasts in the regulation of fetal liver hematopoiesis and stem cell maintenance.
Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.
Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.
Nucleoplasmic ZNF467 condensates boost hematopoietic stem cell engraftment via ICAM1-mediated mechanical reprogramming.
Inhibition of SDE2 promotes autophagy-dependent ferroptosis in multiple myeloma.
Single-cell atlas of AML reveals age-related gene regulatory networks in t(8;21) AML.
Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.
Single-Cell Proteomics of Human Peripheral Blood Mononuclear Cells Exceeding 600 Cells per Day.
EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.
The bone marrow niche and hematopoietic system are distinctly remodeled by CD45-targeted astatine-211 radioimmunotherapy.
Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
THY1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria.
Immune cells adapt to distinct stem cell niches to govern tissue homeostasis.
Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.

Nat Commun. 2026 Feb 12. 17(1): 1645

Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.

Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki.

"Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5-/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5-/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses- including chromatin accessibility, transcriptomics, and metabolomics-reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5-/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.

DOI: https://doi.org/10.1038/s41467-026-69424-x
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702390. [Epub ahead of print]

YY1-Mediated Polycomb Group Function Safeguards Hematopoietic Stem Cells from Premature Aging.

Sahitya Saka, Junki P Lee, Yinghua Wang, Peng Liu, Yunxia Liu, Courtney Hong, Ashley Kuehnl, Lixin Rui, Michael L Atchison, Xuan Pan.

Hematopoietic stem cells (HSCs) undergo functional decline with age, characterized by myeloid-biased differentiation, loss of quiescence, and altered metabolic homeostasis. The molecular mechanisms driving these changes remain incompletely understood. Yin Yang 1 (YY1) is a multifunctional transcription factor and mammalian Polycomb group (PcG) protein that recruits PcG complexes to specific genomic loci via its 26-amino acid REPO (Recruitment of Polycomb) domain. To define the role of YY1 PcG function in adult HSCs, we generated a conditional YY1 REPO domain knockout mouse model ( Yy1 -/ΔREPO ). Deletion of the REPO domain led to premature HSC aging, with expansion of immunophenotypic HSCs but loss of long-term self-renewal capacity. Yy1 -/ΔREPO HSCs exhibited myeloid-biased output, expansion of myeloid-primed multipotent progenitors, increased myeloid colony formation, and an elevated myeloid-to-lymphoid ratio in peripheral blood. These cells displayed reduced quiescence, elevated reactive oxygen species, increased mitochondrial oxidative capacity, and enhanced β-galactosidase activity-hallmarks of cellular aging. RNA-seq demonstrated dysregulation of gene networks governing HSC metabolism. Together, these findings establish YY1 PcG activity as a key epigenetic mechanism that preserves metabolic quiescence, sustains long-term self-renewal, and delays HSC aging. Our studies reveal a fundamental PcG-dependent epigenetic mechanism that dictate cell fate decisions and function decline during HSC aging.

DOI: https://doi.org/10.64898/2026.01.28.702390
Nat Cell Biol. 2026 Feb 11.

Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.

Ayşegül Erdem, Claudia Morganti, Haruhito Totani, Nick van Gastel, Keisuke Ito.

Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.

DOI: https://doi.org/10.1038/s41556-026-01872-5
Dev Cell. 2026 Feb 11. pii: S1534-5807(26)00034-1. [Epub ahead of print]

Tissue-scale mapping reveals a central role of hepatoblasts in the regulation of fetal liver hematopoiesis and stem cell maintenance.

Anjali Vijaykumar, Patrick M Helbling, Flavian Thelen, Serena Fazio, YeVin Mun, Ana Luisa Pereira, Karolina A Zielińska, Paul Büschl, Thomas Zerjatke, Kathrin Loosli, Stephan Isringhausen, Bjoern Menze, Takashi Nagasawa, Ingo Roeder, Alvaro Gomariz, Markus G Manz, Tomomasa Yokomizo, César Nombela-Arrieta.

  During embryonic development, fetal liver (FL) tissues transiently provide a fertile microenvironment for the maturation and expansion of fetal progenitors and hematopoietic stem cells (HSCs). Nonetheless, the cellular composition of FL HSC niches remains underexplored. Using 3D microscopy, bulk mRNA sequencing (mRNA-seq), flow cytometry, and transgenic mouse models, we mapped the spatiotemporal dynamics of niche cells and HSCs during FL development. At peak hematopoiesis, hepatoblasts, endothelial cells, and mesenchymal stromal cells pervasively expressed pro-hematopoietic cytokines throughout FL tissues. Yet, hepatoblasts were spatially dominant, abundantly expressed niche factors, and regulated HSC expansion and erythropoiesis through production of KIT ligand. Subsequent FL remodeling driven by hepatoblast differentiation led to the rapid downregulation of supportive cues and contraction of hematopoietic niches, coinciding with HSC exit toward emergent marrow tissues. Spatial mapping further showed that HSCs and progenitors were dispersed across the parenchyma, following no clear spatial biases within the FL microanatomy yet exhibiting local clustering.

Keywords:  3D quantitative imaging; hematopoietic stem cells; hepatoblasts; niches

DOI:  https://doi.org/10.1016/j.devcel.2026.01.011
bioRxiv. 2026 Jan 28. pii: 2026.01.27.702029. [Epub ahead of print]

Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.

Yuanyuan Xue, Salma Merchant, Amanda Reyes, Maowu Luo, Ruixuan Zhang, Trevor Tippetts, Gerik Grabowski, Tai Ngo, Yanan Zhang, Zhiguo Shang, Nisi Jiang, Elise Jeffery, Yafeng Li, Tao Wei, Wen Gu, Liming Du, Ralph J DeBerardinis, Kevin M Dean, Thomas P Mathews, Daniel Lucas, Zhiyu Zhao, Sean J Morrison.

Leptin Receptor-expressing (LepR + ) stromal cells in the bone marrow are a critical source of growth factors for the maintenance of hematopoietic stem cells (HSCs) and most restricted hematopoietic progenitors. An important unresolved question is whether they also regulate terminal differentiation in some hematopoietic cells. We found that LepR + cells promote thrombopoiesis by synthesizing the chemokine CXCL14, which is expressed in the bone marrow by a subset of LepR + cells. Cxcl14 -expressing LepR + cells extend fine processes that wrap around perisinusoidal megakaryocytes. Deletion of Cxcl14 from LepR + cells did not significantly alter HSC function or most aspects of bone marrow hematopoiesis, including megakaryocyte generation; however, it significantly reduced the numbers of proplatelet-forming megakaryocytes in the bone marrow and platelets in the blood. CXCL14 promoted platelet formation by remodeling lipid metabolism in megakaryocytes, increasing fatty acid transporter expression and enabling megakaryocytes to use more polyunsaturated fatty acids from the circulation. A high fat diet rescued the formation of proplatelet-forming megakaryocyte and platelets in Lepr-cre; Cxcl14 fl/fl mice. CXCL14 protein was sufficient to promote platelet formation by megakaryocytes in vitro and in vivo. LepR + cells thus create a perisinusoidal niche for thrombopoiesis by producing CXCL14, which regulates lipid metabolism and terminal differentiation in megakaryocytes.
Key points: Leptin Receptor + stromal cells regulate terminal differentiation in megakaryocytes in addition to maintaining stem and progenitor cells CXCL14 from Leptin Receptor + cells promotes the formation of platelets by remodeling lipid metabolism in megakaryocytes in the bone marrow.

DOI: https://doi.org/10.64898/2026.01.27.702029
iScience. 2026 Feb 20. 29(2): 114738

Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.

Stephanie G Moreno, Federica Ferri, Daniel Lewandowski, Vilma Barroca, Saiyiramii Devanand, Nathalie Dechamps, Paul-Henri Romeo, Nathalie Gault.

  How hematopoietic stem cells (HSCs) respond to low doses of radiation currently used in medicine is largely unknown. Here, we show that HSC exposed to a single 20 mGy dose of irradiation (20 mGy-HSC) exhibit, when proliferating, oxidative stress and altered metabolism associated with increased mitochondrial reactive oxygen species and mitochondrial Ca2+ overload. These mitochondrial defects arise from immediate and sustained endoplasmic reticulum (ER) stress, induced by proliferative 20 mGy-HSC through the activation of the eIF2α-ATF4 branch of the unfolded protein response (UPR). The ER stress is heritable and leads, in long-term quiescent 20 mGy-HSC, to the activation of the IRE1α-Xbp1 branch of UPR, which fails to restore ER homeostasis, resulting in a decreased long-term HSC pool. Finally, we show that this heritable ER stress leads to global DNA hypomethylation, partially reversed by the early inhibition of ER stress. Our studies illuminate how adaptive ER stress responses can lead to mitochondrial defects and HSC dysfunctions.

Keywords:  Cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.114738
Blood. 2026 Feb 11. pii: blood.2025031247. [Epub ahead of print]

Nucleoplasmic ZNF467 condensates boost hematopoietic stem cell engraftment via ICAM1-mediated mechanical reprogramming.

Yandan Chen, Jinghao Shen, Zaisheng Lin, Qingwei Ding, Xiashiyao Zhang, Meng Zhang, Haoxiang Yang, Han Yao, Sheng Liu, Jun Wan, Shize Liu, Xiaopeng Jia, Xiaodong Wang, Uet Yu, Siguo Hao, Muqing Cao, Hongyuan Jiang, Bin Guo.

Hematopoietic stem cell (HSC) transplantation is a life-saving therapy for immune deficiencies and hematologic malignancies, but its efficacy is limited by poor engraftment. Therapeutic enhancement of HSC grafts requires deeper insight into the intrinsic determinants of their regenerative capacity. Here, we identify mechanical robustness as a critical feature distinguishing human HSCs from multipotent progenitors (MPPs). Through integrative biomechanical and transcriptomic profiling, we show that ZNF467 is a key regulator of HSC mechanical integrity. Loss of ZNF467 disrupts HSC mechanical fitness and abolishes long-term engraftment. Conversely, an engineered phase-separating ZNF467 variant enhanced mechanical strength and engraftment by activating a mechanoresponsive transcriptional program, including upregulation of ICAM1. ICAM1+ HSPCs exhibit superior biomechanical properties and improved engraftment efficiency. Furthermore, phase separation activity of nucleoplasmic ZNF467 (npZNF467) is crucial for its mechanical reprogramming function, and ectopic npZNF467 expression enhances the engraftment capacity of MPPs. Our findings establish biomechanical regulation as an important determinant of stem cell identity and reveal new strategies for engineering stem cells with enhanced regenerative capacity.

DOI: https://doi.org/10.1182/blood.2025031247
Redox Biol. 2026 Jan 16. pii: S2213-2317(26)00005-4. [Epub ahead of print]91 104007

Inhibition of SDE2 promotes autophagy-dependent ferroptosis in multiple myeloma.

Liang Xia, Jing Bao, Xiao-Wen Chen, Yu-Chen Zhao, Xiang Wang, Yu Zheng.

   BACKGROUND: Multiple myeloma (MM) is an incurable plasma cell malignancy with high relapse rate. Recent studies have implicated dysregulated autophagy and ferroptosis in MM progression; however, the molecular links remain elusive. This study investigated the role of SDE2, a ubiquitin-like protein overexpressed in MM, in modulating autophagy-ferroptosis crosstalk via ATG5 degradation with the aim of identifying novel therapeutic targets.
METHODS: Using bioinformatic analysis of TCGA data, we identified SDE2 as a prognostic marker in MM. Functional validation included Western blot, co-immunoprecipitation, and ubiquitination assays in MM cell lines (H929, RPMI8226, OPM-2, and KMS-11) and patient-derived samples. Transwell migration, soft agar colony formation, and flow cytometry were used to assess cellular phenotypes. In vivo efficacy was tested using xenograft models.
RESULTS: SDE2 overexpression correlates with poor MM prognosis and promotes tumor cell survival, migration, and proliferation. Mechanistically, SDE2 binds to ATG5, facilitating K48-linked ubiquitination and proteasomal degradation, thereby suppressing autophagy and ferroptosis. Knockdown of SDE2 restored ATG5 levels, reactivated autophagy, and sensitized MM cells to ferroptosis. Combined SDE2 silencing and pharmacological ATG5/7 activation (Antitumor agent-82) synergistically suppressed tumor growth in vitro and in vivo.
CONCLUSION: The SDE2-ATG5 axis serves as a critical regulator of the autophagy-ferroptosis crosstalk in MM. Targeting SDE2 restores ATG5-dependent autophagy, activates ferroptosis, and inhibits tumor growth. These findings suggest a novel therapeutic strategy that combines SDE2 inhibitors with autophagy agonists, potentially offering clinical benefits in MM treatment. This study provides further insight into autophagy-dependent ferroptosis in other malignancies.

Keywords:  ATG5; Autophagy; Ferroptosis; Multiple myeloma; SDE2; Ubiquitination

DOI:  https://doi.org/10.1016/j.redox.2026.104007
Elife. 2026 Feb 11. pii: RP104978. [Epub ahead of print]14

Single-cell atlas of AML reveals age-related gene regulatory networks in t(8;21) AML.

Jessica Whittle, Stefan Meyer, Georges Lacaud, Syed Murtuza-Baker, Mudassar Iqbal.

  Acute myeloid leukemia (AML) is characterized by cellular and genetic heterogeneity, which correlates with clinical course. Although single-cell RNA sequencing (scRNA-seq) reflects this diversity to some extent, the low sample numbers in individual studies limit the analytic potential when comparing specific patient groups. We performed large-scale integration of published scRNA-seq datasets to create a unique single-cell transcriptomic atlas for AML (AML scAtlas), totaling 748,679 cells, from 159 AML patients and 51 healthy donors from 20 different studies. This is the largest single-cell data resource for human AML to our knowledge, publicly available at https://cellxgene.cziscience.com/collections/071b706a-7ea7-47a4-bddf-6457725839fc. This AML scAtlas allowed investigations into 20 patients with t(8;21) AML, where we explored the clinical importance of age, given the in-utero origin of pediatric disease. We uncovered age-associated gene regulatory network (GRN) signatures, which we validated using bulk RNA sequencing data to delineate distinct groups with divergent biological characteristics. Furthermore, using an additional multiomic dataset (scRNA-seq and scATAC-seq), we validated our initial findings and created a de-noised enhancer-driven GRN reflecting the previously defined age-related signatures. Applying integrated data analysis of the AML scAtlas, we reveal age-dependent gene regulation in t(8;21) AML, potentially reflecting immature/fetal HSC origin in prenatal origin disease vs postnatal origin. Our analysis revealed that BCLAF1, which is particularly enriched in pediatric AML with t(8;21) of inferred in-utero origin, is a promising prognostic indicator. The AML scAtlas provides a powerful resource to investigate molecular mechanisms underlying different AML subtypes.

Keywords:  AML; AML-ETO; Atlas; age-related disease; cancer biology; computational biology; gene regulatory network; human; single cell; systems biology

DOI:  https://doi.org/10.7554/eLife.104978
Cell Chem Biol. 2026 Feb 10. pii: S2451-9456(26)00026-7. [Epub ahead of print]

Metabolic control of innate immune activation in TET2-mutant clonal hematopoiesis.

Peter Geon Kim, Christopher B Hergott, Aidan P Miller, Amy Deik, Meaghan Boileau, Kevin Bullock, Kerry A Pierce, Angelina H Choy, Wesley Shin, Marie McConkey, Justin Loke, Birgitta A Ryback, Michael N Trinh, Justine C Rutter, Hong Yue, Hojong Yoon, Paul Park, Shourya S Roy Burman, Matthew G Vander Heiden, Eric S Fischer, Scott A Armstrong, Clary Clish, Benjamin L Ebert.

  Somatic mutations in TET2 drive hyper-inflammation in clonal hematopoiesis of indeterminate potential (CHIP), but the molecular link between TET2 inactivation and myeloid immune activation remains unclear. We used in vivo genome-wide genetic perturbations enabled by ultra-diverse barcoding in primary wild-type (WT) or Tet2 knockout (KO) Cas9+ hematopoietic stem-progenitor cells (HSPCs) to elucidate the basis of Tet2 KO inflammation. We uncover a metabolic circuit by which Tet2 restrains O-linked N-acetylglucosamine (O-GlcNAc) glycosyltransferase (Ogt), a Tet2 binding partner and metabolic sensor. Tet2 loss disrupts this inhibitory Tet2-Ogt interaction, and dysregulated Ogt facilitates widespread H3K4 trimethylation including lipid-related gene loci and inflammatory lipid droplet formation. We identified that ATP citrate lyase (Acly) is decorated with O-GlcNAc and is a critical node for lipid accumulation and inflammation in Tet2 KO. These findings reveal that Tet2 suppresses inflammation by gating nutrient-responsive chromatin remodeling and nominate metabolic interventions to restrain inflammatory disease in TET2-mutant clonal hematopoiesis.

Keywords:  Tet2-mutant inflammation; clonal hematopoiesis; hematopoietic stem-progenitor screens; lipid droplets

DOI:  https://doi.org/10.1016/j.chembiol.2026.01.006
bioRxiv. 2026 Feb 03. pii: 2026.02.01.703169. [Epub ahead of print]

Single-Cell Proteomics of Human Peripheral Blood Mononuclear Cells Exceeding 600 Cells per Day.

James M Fulcher, Yumi Kwon, Pranav Dawar, Rashmi Kumar, Sarah M Williams, Patricia Miller, Andrey Liyu, Liang Chen, Daniel J Orton, Heather M Olson, Fengchao Yu, Alexey I Nesvizhskii, Julie Fortier, Ravi Vij, Reyka Jayasinghe, Li Ding, Ying Zhu, Ljiljana Paša-Tolić.

Single-cell proteomic (scProteomic) measurements of peripheral blood mononuclear cells (PBMCs) are of considerable value in human health, given their involvement in the maintenance of healthy and diseased states. However, the high heterogeneity and relatively small size of immune cell types demand maximal throughput and sensitivity in proteomic measurements that have yet to be fully realized. Here, we describe an approach that addresses sensitivity and throughput through the implementation of Real-Time spectral Library Searching (RTLS), TMTpro 32-plex labelling, an updated nested-nanodroplet processing in One pot for Trace Samples (N2), and a dual-column liquid chromatography system. By prioritizing tandem mass spectrometry (MS2) features with high similarity to library spectra, RTLS enables greater identification depth and feature reproducibility than a standard shotgun MS2 approach in low-input and single-cell samples. The platform permitted 660 single PBMCs to be measured per day, with an average of 750 protein identifications per cell and 1,648 proteins in total, achieving the necessary throughput and depth to characterize immune cell populations. Application of this scProteomic method and a new cell typing informatics approach to 2,130 PBMCs enabled the identification of both major and low-frequency cell types (∼1-2%), as well as associated proteomic markers.

DOI: https://doi.org/10.64898/2026.02.01.703169
Haematologica. 2026 Feb 12.

EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.

Yigen Li, Amy Wilson, Yakinthi Chrisochoidou, Shannon Martin, Sarah Bird, Salomon Morales, Marc Leiro, Zuza Kozik, Nicholas T Crump, Theodoros I Roumeliotis, Jyoti Choudhary, Charlotte Pawlyn.

Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CELMoDs), targeting the IKZF1/IKZF3-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients have primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression free survival from diagnosis. EZH2 inhibitors have been studied as a single agent in myeloma and in combination treatments to overcome drug resistance in other malignancies. In this study KMS-11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, demonstrating persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CELMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CELMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition appears specific to IMiDs/CELMoDs, is CRBN-dependent and rescued by IRF4 overexpression. Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

DOI: https://doi.org/10.3324/haematol.2025.288024
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025017065. [Epub ahead of print]

The bone marrow niche and hematopoietic system are distinctly remodeled by CD45-targeted astatine-211 radioimmunotherapy.

Matthew W Hagen, Nicollette J Setiawan, Shannon L Dexter, Kelsey A Woodruff, Francesca Lois K Gaerlan, Taylor M Billings, Johnnie J Orozco, Christina M Termini.

Radioimmunotherapy (RIT) is used to treat patients with hematological malignancies known to infiltrate the bone marrow (BM) microenvironment. RIT uses target-specific monoclonal antibodies stably conjugated to radionuclides to deliver cytotoxic radiation to cells of interest. While RIT is effective at delivering radiation to cancer cells, normal tissue is also exposed to radiation upon RIT, the consequences of which are largely unknown. Here, we studied the cellular and molecular effects of CD45-targeted astatine-211 (211At) RIT, IgG non-targeted 211At RIT, and Cesium-137 total-body irradiation (TBI) on hematopoietic cells and their BM niche in wild-type immunocompetent mice. Relative to non-targeted RIT or TBI, CD45-targeted RIT significantly delayed hematopoietic regeneration overall in the peripheral blood and BM and reduced hematopoietic stem/progenitor cell recovery and colony-forming ability. While BM endothelial cells (ECs) do not express the CD45 antigen, CD45-targeted RIT significantly depleted BM ECs compared to non-targeted RIT or TBI. RNA sequence analysis revealed significantly different transcriptomic profiles of BM ECs from CD45-RIT-treated mice compared to non-targeted RIT or TBI. ECs from CD45-RIT-treated mice, but not TBI or IgG-RIT-treated mice, were transcriptionally enriched for growth factor signaling pathways compared to untreated mice. Bone marrow soluble growth factor expression remained upregulated in CD45-RIT-treated mice 28 days post-treatment compared to non-treated mice. Collectively, our study indicates that CD45-targeted RIT severely impacts hematopoietic and EC niche recovery compared to non-targeted approaches. Future studies are required to determine the long-term consequences of such RIT-driven effects on BM niche physiology and how BM niche reprogramming by RIT affects cancer cells.

DOI: https://doi.org/10.1182/bloodadvances.2025017065
Sci Signal. 2026 Feb 10. 19(924): eadw5054

Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia.

Jaewoong Lee, Ruifeng Sun, Kohei Kume, Mark E Robinson, Zhangliang Cheng, Kadriye Nehir Cosgun, Ning Ma, Christian Hurtz, Huimin Geng, Selina M Luger, Mark R Litzow, Elisabeth Paietta, Jianjun Chen, Nagarajan Vaidehi, Markus Müschen.

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25+ leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB-mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry-based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase-driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

DOI: https://doi.org/10.1126/scisignal.adw5054
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
Nat Cell Biol. 2026 Feb 12.

THY1+ cancer stem cells drive metastasis through a pseudohypoxic state shaped by neutrophil-derived mitochondria.

Wen-Hua Wan, Pei-Lin Li, Wen-Jie Cao, Zheng-Xi Li, Yu-Qi Xin, Jun-Cheng Wang, Lei Chen, Lianxin Liu, Muyan Cai, Limin Zheng, Xiang-Ming Lao, Yuan Wei, Dong-Ming Kuang.

Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models, we identify THY1⁺ CSCs as the key drivers of metastasis and uncover a previously unrecognized 'pseudohypoxic' state (independent of classical hypoxia) as a central regulatory factor. The self-renewal of THY1⁺ CSCs is maintained by IL-6-MYC signalling. Upon encountering neutrophils, THY1⁺ CSCs activate the THY1-Mac1 axis, triggering the Src-Akt/Erk pathway, Rac1 activation and a migrasome-dependent process that induces neutrophils to expel reactive oxygen species-enriched damaged mitochondria. THY1 signalling further enhances macropinocytosis, enabling CSCs to internalize these mitochondria and adopt a pseudohypoxic state, thereby facilitating CSC metastasis. Notably, targeting the IL-6-Myc, THY1-Mac1 or Src-Akt/Erk signalling pathways effectively suppresses pseudohypoxia-driven CSC metastasis. These findings unveil previously unexplored mechanisms by which CSCs undergo metastasis, offering potential strategies to combat tumour metastasis and improve cancer prognosis.

DOI: https://doi.org/10.1038/s41556-026-01876-1
bioRxiv. 2026 Jan 31. pii: 2026.01.28.701831. [Epub ahead of print]

Immune cells adapt to distinct stem cell niches to govern tissue homeostasis.

S Martina Parigi, Sairaj M Sajjath, Charlotte J Bell, Shaopeng Yuan, Vitoria M Olyntho, Alain R Bonny, Sandra Nakandakari-Higa, Sergio A Lira, Daniel Mucida, Gabriel D Victora, Elaine Fuchs.

In adult tissues, epithelial stem cells exist within distinct residences, each endowing them with exclusive instructions for regenerative fitness under homeostasis and stress. Key components of these 'niches' are immune cells, which classically protect the host against external and internal threats. Whether and how stem cell:immune cell crosstalk contributes to normal tissue biology remains less clear. Here, we discover functional adaptation of resident lymphocytes within two distinct skin stem cell niches and show that through this communication, each niche adjusts to meet diverse tissue demands. In the upper hair follicle, where microbial load is high, T cells express lymphotoxin-β and stimulate adjacent receptor-positive epithelial stem cells to form an immune-competent niche that controls microbial expansion. By contrast, in the epidermis, these T cells produce amphiregulin to maintain continuous stem cell reconstitution of the skin's barrier. Concomitantly, they express the immune checkpoint protein 'LAG-3', which autorestricts lymphocyte numbers, and hence amphiregulin levels, thereby preventing over-proliferative responses. Finally, when epidermal T cells are absent, dermal lymphocytes restore the imbalance by colonizing and adapting to their new niche. Our findings unveil functional specialization and homeostatic resilience of immune-stem cell niches, each tailored to suit the demands of distinct tissue microenvironments.

DOI: https://doi.org/10.64898/2026.01.28.701831
Nat Commun. 2026 Feb 12.

Glycocalyx micro- and nanodomains in cell-cell and cell-matrix interactions revealed by enhanced click chemistry.

Daan Smits, Johannes A M Damen, Tianfu Li, Floris L van Delft, Bauke Albada, Peter Friedl.

The glycocalyx consists of glycoproteins, glycolipids and extracellular polysaccharides at the cell surface which mediate viscoelastic and electrostatic barrier function. In molecular interactions, the glycocalyx is thought to segregate locally to facilitate receptor-ligand binding, yet high-resolution maps of glycocalyx domains in cell-cell and cell-matrix interactions are lacking. We here apply TMTH-sulfoximine (THS)-based biorthogonal chemistry in live-cell culture and demonstrate enhanced glycocalyx detection, compared to established dibenzocyclooctyne-based labeling. Using superresolution microscopy in cancer cells, we identify micron-scale diminished glycocalyx in cell-cell contacts and depletion in protrusions at the leading and trailing edges and membrane blebs when cells invade 3D fibrillar matrix. At contacts to collagen fibrils, focal integrin clusters segregate ~350 nm outward from the glycocalyx level, forming adhesion sites of low glycocalyx content. Thus, we identify micro- and nanodomains with altered glycocalyx density using THS-based bioorthogonal labeling of live cells, implicating local glycocalyx downregulation in functional cell-cell and cell-matrix interactions.

DOI: https://doi.org/10.1038/s41467-026-69242-1