bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–03–29
twenty-six papers selected by
William Grey, University of York
  1. Hematopoietic stem and progenitor cell hierarchy is established by thrombopoietin-driven neonatal hematopoiesis.
  2. Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
  3. From bud to stem: dynamics of hematopoietic stem cells that drive homing and mobilization.
  4. Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
  5. Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
  6. CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target.
  7. A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia.
  8. Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation.
  9. PPT1 regulates mitochondrial redox by depalmitoylating PRDX3.
  10. Development of Hematopoietic Stem Cell-targeted LNPs through Lipid Composition Optimization.
  11. Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.
  12. The interaction between NPMc+ and Orai1 induces abnormal calcium influx to facilitate leukemogenesis.
  13. Engineered MSCs enable bone marrow-targeted immunomodulation.
  14. Dynamic epigenetic regulation of BCLAF1 splicing in acute myeloid leukemia.
  15. Solubility based mechanistic profiling of combinatorial drug therapy.
  16. Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.
  17. Chemotherapy-driven expression of WNT ligands in bone marrow stromal cells contributes to chemoresistance in acute lymphoblastic leukaemia.
  18. The cytoplasm of living cells can sustain transient and steady intracellular pressure gradients.
  19. Noncanonical role of KDM5C in conferring bortezomib resistance via the PERK‒Nrf2 axis in multiple myeloma.
  20. Enhanced dynamic risk stratification of smoldering multiple myeloma.
  21. Disrupting adaptive proteostasis to overcome proteasome inhibitor resistance.
  22. ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances.
  23. The RING E3 Ligase RLIM Drives Oxidative Stress-Induced Stem Cell Dysfunction through MDM2-p53 Signaling.
  24. A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.
  25. The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
  26. Survey of the human proteostasis network: the ubiquitin-proteasome system.
  1. Stem Cell Reports. 2026 Mar 26. pii: S2213-6711(26)00076-7. [Epub ahead of print] 102865
    Hematopoietic stem and progenitor cell hierarchy is established by thrombopoietin-driven neonatal hematopoiesis.
    Makiko Mochizuki-Kashio, Ayano Yahagi, Tomomasa Yokomizo, Terumasa Umemoto, Toshio Suda, Ayako Nakamura-Ishizu.
      The cytokine thrombopoietin (THPO) promotes both self-renewal and cell cycle quiescence of adult bone marrow (BM) hematopoietic stem cells (HSCs). It remains unclear how THPO differentially regulates HSC expansion versus quiescence and whether it influences the broader BM hematopoietic hierarchy, particularly multipotent progenitor cells (MPPs), which express MPL, the receptor for THPO. Adult constitutional Thpo-knockout mice exhibited significant decrease in both HSC and MPP numbers, yet single-cell RNA sequence-based genetic changes were prominent only in HSCs. Induced deletion of Thpo in adult mice showed that THPO primarily maintains adult BM HSC numbers by inhibiting apoptosis. Thpo deficiency-driven reduction of adult BM MPPs was attributed to the shortage of expansion and differentiation of HSCs during neonatal BM hematopoiesis. Drug-mediated enhancement of THPO signaling in neonatal Thpo-deficient mice rescued adult BM progenitor cell numbers but not HSC apoptosis. THPO function is thus limited during adult hematopoiesis but is critical during neonatal development to establish a structured HSC and MPP hierarchy.
    Keywords:  bone marrow hematopoiesis; hematopoietic hierarchy; hematopoietic stem and progenitor cell; neonatal hematopoiesis; thrombopoietin
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102865
  2. Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]
    Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
    Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.
      Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.
    DOI:  https://doi.org/10.1182/blood.2025031552
  3. Curr Opin Hematol. 2026 Mar 06.
    From bud to stem: dynamics of hematopoietic stem cells that drive homing and mobilization.
    Farnaz Razmkhah, Stephanie N Hurwitz.
       PURPOSE OF REVIEW: Hematopoietic stem and progenitor cells (HSPCs) ensure lifelong hematopoiesis through their unique ability to self-renew and differentiate into all blood cell lineages. Their localization within bone marrow niches and the ability to traffic between hematopoietic and peripheral tissues during development and adult life are governed by complex signaling networks involving adhesion molecules, chemokines, metabolic cues, and niche-derived factors.
    RECENT FINDINGS: This review explores the molecular and cellular mechanisms that regulate HSPC homing, retention, and mobilization during development, homeostasis, and therapeutic transplantation. In particular, we focus on intrinsic, dynamic properties of HSPCs that guide developmental transitions in trafficking behavior from fetal to adult niches, physiological egress under steady-state conditions, and dictate outcomes of forced mobilization and bone marrow homing during therapeutic collection and transplantation.
    SUMMARY: These findings highlight HSPC trafficking as a highly regulated and adaptable process integrating intrinsic stem cell states with extrinsic niche cues. Understanding these mechanisms provides a conceptual framework for improving strategies to enhance HSPC mobilization, homing, and engraftment toward optimizing hematopoietic stem cell therapies.
    Keywords:  chemokine receptor; hematopoietic stem cells; homing; mobilization; transplantation
    DOI:  https://doi.org/10.1097/MOH.0000000000000922
  4. Cell Stem Cell. 2026 Mar 23. pii: S1934-5909(26)00081-0. [Epub ahead of print]
    Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis.
    Ashley N Kamimae-Lanning, Jill M Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K Wilson, Felix A Dingler, Rebecca L Cordell, Meng Wang, Christopher L Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F T R de Bruijn, Juan I Garaycoechea, Jean Soulier, Thomas Höfer, Ketan J Patel.
      DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.
    Keywords:  Fanconi anemia; HSC attrition; bone marrow failure; clonal hematopoiesis; endogenous DNA damage; formaldehyde; neutral drift; somatic evolution; stem cell aging
    DOI:  https://doi.org/10.1016/j.stem.2026.02.011
  5. bioRxiv. 2026 Mar 02. pii: 2026.02.28.707294. [Epub ahead of print]
    Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
    Katia E Niño, Vera Adema, Alyx E Gray, Courtney M Cowan, Wolfgang E Schleicher, Mohsen Hosseini, Sierra N Bennett, Sweta B Patel, Steven Moreira, Etienne Danis, Feiyang Ma, Hsin-Ying Lin, Tracy N Young, Colin A Anderson, Devyani Sharma, Angelica Varesi, Marie-Dominique Filippi, Keisuke Ito, Meelad M Dawlaty, Gang Huang, Julie A Reisz, Stephanie Z Xie, Steven M Chan, Lin Tan, Guillermo Garcia-Manero, Kelly Chien, Irene Gañan Gomez, Angelo D'Alessandro, Simona Colla, Eric M Pietras.
      The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2 . Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2 -deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2 -deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2 -deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage.
    Statement of Significance: This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.
    DOI:  https://doi.org/10.64898/2026.02.28.707294
  6. Leukemia. 2026 Mar 23.
    CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target.
    Stefan Forster, Chantal Reinhardt, Maxime Boy, Adrian Wegmüller, Alessio Hinrichsen, Christian M Schürch, Frido K Brühl, Falko Fend, Alexandar Tzankov, Marie-Noëlle Kronig, Michaela Römmele, Angéline Glück, Benjamin Lüscher, Myriam Legros, Ulrike Bacher, Katja Seipel, Thomas Pabst, Ramin Radpour, Carsten Riether, Adrian F Ochsenbein.
      The increasing therapeutic options for multiple myeloma (MM) have significantly improved long-term survival for many patients. However, disease progression remains inevitable due to the emergence of drug-resistant myeloma cell populations, often culminating in extramedullary disease manifestations. In this study, we identified CD70-expressing myeloma cells as critical drivers of disease progression and propagation. CD70 expression in MM cells is an independent negative prognostic factor for overall survival. Mechanistically, CD70/CD27 signaling activates the MAPK/ERK and Wnt signaling pathways in MM cell lines and primary patient-derived MM samples, promoting increased cell cycling and proliferation. This proliferative advantage results in elevated CD70 expression in advanced MM stages, particularly in extramedullary myeloma. Functional inhibition of CD70/CD27 signaling, achieved either by generating CD70-knockout primary MM cells or with blocking monoclonal antibodies, completely abrogated tumor growth in xenotransplantation models. Furthermore, the ADCC-enhanced anti-CD70 antibody, cusatuzumab, demonstrated high efficacy in treating myeloma in xenotransplantation models. Collectively, these findings underscore the critical role of CD70/CD27 signaling in activating MAPK/ERK and Wnt pathways essential for MM progression. Targeting CD70 with blocking or ADCC-enhanced antibodies represents a promising therapeutic strategy, particularly for advanced MM stages characterized by high CD70 expression.
    DOI:  https://doi.org/10.1038/s41375-026-02899-1
  7. Leukemia. 2026 Mar 25.
    A Perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged acute myeloid leukemia.
    Sajesan Aryal, Brittany M Curtiss, Xinyue Zhou, Rui Lu, Changde Cheng.
      KMT2A-rearranged acute myeloid leukemia is driven by epigenetic dependencies yet remains clinically resistant to therapies targeting individual regulators, indicating that resistance reflects compensatory regulation across an epigenetic network. A systematic understanding of this compensatory network has been lacking. To address this gap, we utilized Perturb-seq screening to systematically map the functional architecture of this network. We uncovered a compensatory epigenetic circuit, where a synergistic hub including KAT6A, Menin, and DOT1L converges to silence a core differentiation program (the 'Myeloid Program'), thereby maintaining leukemic identity. The activity of this program strongly correlated with favorable survival in large patient cohorts. While individual perturbations of hub components only partially derepress this program, their simultaneous pharmacological inhibition collapses the circuit's buffering capacity, leading to robust reactivation of the Myeloid Program and potent synergistic anti-leukemic activity. Our model also shows that disruption of antagonistic regulators of the Myeloid Program, such as the PRC1.1 component PCGF1, confers strong resistance to DOT1L inhibition. Finally, the Myeloid Program is a predictive biomarker, where high baseline activity defined a vulnerable state that could be selectively targeted by MEK, AKT, and mTOR inhibitors. Together, these findings establish a framework for identifying circuit-level epigenetic compensation and for rationally designing precision combination therapies that restore differentiation or target state-dependent vulnerabilities in acute myeloid leukemia.
    DOI:  https://doi.org/10.1038/s41375-026-02917-2
  8. Dev Cell. 2026 Mar 23. pii: S1534-5807(26)00121-8. [Epub ahead of print]
    Hematopoietic stem cells activate a latent differentiation pathway to facilitate recovery after 5-fluorouracil-induced myeloablation.
    Zhen Zhang, Ben Jin, Chenyu You, Ya Li, Li Lin, Jianlong Sun.
      
    DOI:  https://doi.org/10.1016/j.devcel.2026.03.009
  9. Cell Signal. 2026 Mar 20. pii: S0898-6568(26)00154-3. [Epub ahead of print]143 112502
    PPT1 regulates mitochondrial redox by depalmitoylating PRDX3.
    Gengjun Zhu, Lifang Jin, Weizhang Shen, Xiaofeng Li, Xing Tian, Yuhua Zhang, Ning Liu.
      Multiple myeloma (MM) remains an incurable hematological cancer, with an enhanced antioxidant capacity that fuels disease progression. Peroxiredoxins (PRDXs), central players of redox homeostasis, are overexpressed in cancers including MM, and their high expression correlates with poor prognosis. However, the detailed mechanisms underlying how PRDXs are regulated in the context of redox homeostasis and MM pathogenesis remain unclear. In this study, we identify PPT1 as a promising therapeutic target that sustains PRDX3 antioxidant activity by catalyzing its depalmitoylation at the catalytic cysteine (C108). We demonstrated that genetic or chemical inhibition of PPT1 induced cytotoxicity in MM cells through a mechanism involving elevated mitochondrial reactive oxygen species (mtROS). Furthermore, PPT1 inhibition significantly suppressed the growth of xenograft tumors and increased the level of PRDX3 S-palmitoylation. Collectively, our study identifies PPT1 as the bona fide depalmitoylase of PRDX3 and establishes this axis as a promising therapeutic target in MM.
    Keywords:  Depalmitoylation; Mitochondrial redox homeostasis; Multiple myeloma; PPT1; PRDX3
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112502
  10. Exp Hematol. 2026 Mar 24. pii: S0301-472X(26)00056-1. [Epub ahead of print] 105423
    Development of Hematopoietic Stem Cell-targeted LNPs through Lipid Composition Optimization.
    Takamasa Hiraki, Keita Yamamoto, Yu-Hsuan Chang, Chika Nakayama, Mark Wunderlich, Benjamin Mizukawa, Emi Nozaki, Daiki Kiribuchi, Hidekazu Saito, Mitsuko Ishihara-Sugano, Motohiro Kato, Susumu Goyama.
      Hematopoietic stem cell (HSC)-targeted gene editing holds significant potential for treating hereditary hematopoietic disorders, yet the efficient and safe delivery of gene editing tools into HSCs remains a critical challenge. Lipid nanoparticles (LNPs) have emerged as a promising platform for nucleic acid delivery; however, achieving high transfection efficiency in HSCs remains challenging. In this study, we developed HSC-targeted LNPs by integrating Bayesian optimization with our functional amino lipids. The optimized LNPs exhibited markedly improved transfection efficiency while preserving cell viability, surpassing earlier formulations. Using these LNPs, we achieved ex vivo TP53 gene editing in cord blood (CB) CD34⁺ cells with up to 40% on-target editing efficiency. Additionally, one LNP demonstrated efficient RNA delivery into primary human monocytic leukemia cells. These results highlight the potential of machine learning-guided LNP design for advancing HSC-targeted therapies and underscore the promise of LNP-based gene editing platforms to treat hereditary and malignant hematopoietic disorders.
    Keywords:  Genome Editing; Hematopoietic Stem Cell; Lipid Nanoparticle; Machine Learning
    DOI:  https://doi.org/10.1016/j.exphem.2026.105423
  11. Cell Death Discov. 2026 Mar 24.
    Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.
    Manuela Albuquerque de Melo, Brunno Gilberto Santos de Macedo, Diego A Pereira-Martins, Antônio Bruno Alves-Silva, Natasha Peixoto Fonseca, Livia Bassani Lins de Miranda, Cleide Lucia Araújo Silva, Priscila Santos Scheucher, Jan Jacob Schuringa, João Agostinho Machado-Neto, Fabiola Traina.
      Autophagy induction has recently emerged as a mechanism of resistance to FLT3 inhibitors (FLT3i) in patients with FLT3-ITD mutant acute myeloid leukemia (AML). Here, we assessed the molecular mechanisms of autophagy inhibition associated with FLT3i and its impact on cell survival and pharmacological resistance. In FLT3-ITD AML cell lines (MOLM13 and MV4-11), treatment with first- and second-generation FLT3i (midostaurin and quizartinib, respectively) induced autophagy. Combining FLT3i with autophagy inhibitors further decreased cell viability and increased cell apoptosis in both cell lines and in primary patient samples. Label-free quantification proteomics of MOLM13 cells revealed that RFC4 (Replication Factor C Subunit 4), an autophagy regulator linked to increased chemosensitivity, and GATD3/C21orf33 (Glutamine Amidotransferase Class 1 Domain Containing 3) proteins were upregulated only in the combined group, while 11 proteins mostly associated with chemoresistance were downregulated. In vivo, the combination of midostaurin and autophagy inhibition improved overall survival in MOLM13-transplanted mice. ATG5- (Autophagy Related 5) and ATG7-knockdown (Autophagy Related 7) increased sensitivity to first- and second-generation FLT3i in MOLM13 cells. To investigate the potential of autophagy inhibition in overcoming FLT3i resistance, we generated MV4-11 cells resistant to quizartinib (MV4-11QR). The resistant cell line exhibited higher basal levels of autophagy compared to the parental cell line. The combination of quizartinib and chloroquine demonstrated a synergistic effect in MV4-11QR cells and this effect was associated with greater inhibition of the FLT3 receptor compared to the monotherapies. Therefore, combining FLT3i with autophagy inhibition enhances the FLT3i antileukemic efficacy and overcomes pharmacological resistance.
    DOI:  https://doi.org/10.1038/s41420-026-03037-7
  12. FEBS J. 2026 Mar 24.
    The interaction between NPMc+ and Orai1 induces abnormal calcium influx to facilitate leukemogenesis.
    Wenhao Zhang, Chuangxuan Liang, Lulu Zhang, Xinglin Liu, Zhenyu Zhang, Huarong Guo, Jie Jia, Xin Chen, Hongxin Shang, Xuena Zheng, Jun Qin, Shan Li, Danwen Liu, Fuyun Wu.
      Nucleophosmin 1 (NPM1) is a ubiquitously expressed phosphoprotein, mainly located in the nucleolus. It is overexpressed in solid tumors and considered a key target in cancer therapy. NPM1 mutations are the most common genetic abnormalities in acute myeloid leukemia (AML), where they are found in about 30% of patients. In AML, NPM1 mutations result in the cytoplasmic localization of the mutant protein NPMc+. Although NPM1 mutations are known to drive AML, the underlying mechanisms are not fully understood. In this study, we found that primary leukemia cells from NPM1-mutated AML patients exhibited elevated intracellular calcium levels compared with cells from NPM1 wild-type AML patients. Our investigation revealed that NPMc+ interacts with the calcium channel Orai1, disrupting calcium homeostasis in AML cells. Notably, we identified that the N-terminal region of NPM1 contains a calcium-binding domain that directly interacts with Orai1, facilitating calcium influx. Targeting NPMc+, Orai1, or the NPMc+/Orai1 complex using small-molecule inhibitors significantly reduced calcium influx, inhibited calcium-related signaling pathways, and suppressed the proliferation of NPM1-mutated AML cells. These findings uncover a novel mechanism in which NPMc+ interacts with Orai1, disrupting calcium homeostasis and promoting AML progression. This presents a promising therapeutic strategy targeting the NPMc+/Orai1-mediated calcium imbalance in NPM1-mutated AML.
    Keywords:  NPM1; Orai1; acute myeloid leukemia; calcium influx; calcium signaling
    DOI:  https://doi.org/10.1111/febs.70508
  13. Cell Stem Cell. 2026 Mar 26. pii: S1934-5909(26)00113-X. [Epub ahead of print]
    Engineered MSCs enable bone marrow-targeted immunomodulation.
    Shuyue Xu, Jingwen Xu, Qiqi Yang, Ju Zeng, Mengjie Zhang, Yuge Wu, Zhen Liu, Qun Wang, Qing You, Shiyi Zhang.
      Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSCGlg1) to mimic BM affinity signals. In a myelosuppression model, MSCGlg1 delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSCGlg1 delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.
    Keywords:  BM targeting; MSCs; bone marrow; bone marrow protection; drug delivery; immune therapy; mesenchymal stromal cells; metastatic organotropism; tumor evasion
    DOI:  https://doi.org/10.1016/j.stem.2026.03.003
  14. Cell Death Dis. 2026 Mar 24.
    Dynamic epigenetic regulation of BCLAF1 splicing in acute myeloid leukemia.
    Giulia Sgueglia, Crescenzo Massaro, Annamaria Muro, Ida Lettiero, Erika D'Agostino, Gregorio Favale, Nicla Simonelli, Nunzio Del Gaudio, Vincenzo Carafa, Tommaso De Marchi, Dante Rotili, Sergio Valente, Antonello Mai, Gianluca Sbardella, Mariacarla De Simone, Lucia Altucci, Carmela Dell'Aversana.
      Dysregulation of alternative splicing is increasingly associated with cancer development and tumor progression. BCL2-associated transcription factor 1 (BCLAF1) is involved in a wide range of biological processes and it is continuously being investigated due to its intricate function in tumorigenesis and drug resistance. In acute myeloid leukemia (AML) cell lines, we identified two distinct, unbalanced isoforms of BCLAF1: the full-length isoform, which exhibits oncogenic properties, and the short-length isoform, which seems to act as a tumor suppressor. Treatment with specific epidrugs can re-establish the physiological balance of full- and short-length isoforms, restoring their correct equilibrium. Our results suggest the existence of a newly identified mechanism underlying the regulation of BCLAF1 splicing orchestrated, at least in part, by the interplay between HDAC1 and DNMT3A, and directly correlated with the healthy or cancerous state of hematopoietic cells. Our findings shed light on a novel regulatory axis in AML and highlight the potential of epidrugs to restore normal splicing patterns, paving the way for innovative therapies.
    DOI:  https://doi.org/10.1038/s41419-026-08594-4
  15. Nat Commun. 2026 Mar 25. pii: 2744. [Epub ahead of print]17(1):
    Solubility based mechanistic profiling of combinatorial drug therapy.
    Elham Gholizadeh, Ehsan Zangene, Uladzislau Vadadokhau, Danilo Ritz, Juho J Miettinen, Rabah Soliymani, Marc Baumann, Mathias Wilhelm, Esko Kankuri, Paul A Haynes, Caroline A Heckman, Amir A Saei, Mohieddin Jafari.
      Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed "conjunctional targeting", in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.
    DOI:  https://doi.org/10.1038/s41467-026-70394-3
  16. Mol Cancer Ther. 2026 Mar 26.
    Bortezomib Restores Venetoclax Sensitivity in Acute Myeloid Leukemia Cell Lines with Intrinsic and Acquired Resistance.
    Chengxi Li, Yu-Hsuan Chang, Minori Maki, Ikuko Omori, Naru Sato, Susumu Goyama, Toshio Kitamura, Yutaka Enomoto.
      Venetoclax, a selective BCL-2 inhibitor, effectively induces apoptosis in a wide range of malignancies. Venetoclax-based regimens, combined venetoclax with either hypomethylating agents or low-dose cytarabine, have markedly improved treatment outcomes in elderly patients with acute myeloid leukemia (AML). However, approximately one-third of patients exhibit intrinsic resistance to these regimens, and the majority of initial responders eventually develop acquired resistance. Therefore, intrinsic and acquired resistance to venetoclax-based regimens remains a major barrier to achieving durable clinical responses in AML patients. In this study, we aimed to identify effective treatment strategies to overcome venetoclax resistance. Among drugs tested in this study, we found that bortezomib, a proteasome inhibitor, showed potent synergy with venetoclax in inducing apoptosis in a wide range of AML cell lines, irrespective of RAS or TP53 mutation status. Mechanistically, bortezomib upregulates pro-apoptotic proteins such as NOXA, BIM, and PUMA, which neutralize MCL1 and promote apoptosis. Notably, NOXA upregulation plays a critical role in the efficacy of the combination of venetoclax and bortezomib. Moreover, bortezomib resensitized AML cell lines with acquired resistance to venetoclax, further supporting its role in overcoming therapeutic resistance. Importantly, the combination of bortezomib and venetoclax significantly prolongs the survival of mice inoculated with venetoclax-resistant AML cell line harboring BAX mutations, which are commonly observed in relapsed AML following venetoclax-based regimens and confer resistance to venetoclax by inhibiting BAX-dependent apoptotic pathway. Collectively, this study provides a rationale for venetoclax-bortezomib combination as a potential strategy to overcome venetoclax resistance in certain AML subsets.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0986
  17. Br J Haematol. 2026 Mar 17.
    Chemotherapy-driven expression of WNT ligands in bone marrow stromal cells contributes to chemoresistance in acute lymphoblastic leukaemia.
    Foteini Kalampalika, Amanda Jiménez-Pompa, Raúl Sánchez-Lanzas, Bela Patel, Miguel Ganuza.
      Despite recent advances, treatment outcomes for adults with acute lymphoblastic leukaemia (ALL) remain poor. Although patients often exhibit an initial favourable response to chemotherapy, with substantial clearance of tumour cells, most patients eventually relapse. This indicates the persistence of a chemoresistant ALL subpopulation capable of driving disease regeneration. Growing evidence implicates interactions between leukaemia cells and the bone marrow (BM) niche in this process. Our findings show that BM-derived mesenchymal stem cells (MSCs) and adipocytes (BMAds) promote chemotherapy resistance in ALL cells via activation of the wingless-related integration site (WNT) signalling pathway. Chemotherapy-treated co-cultures of MSCs/BMAds and ALL cells exhibited upregulation of several WNT ligands in the stromal compartment. Notably, pharmacological inhibition of WNT signalling abrogated the stromal-mediated chemoprotection and enhanced ALL cell apoptosis in vitro. In vivo, WNT inhibition in a p185BCR-ABLArf-/- B-ALL mouse model sensitised leukaemia cells to chemotherapy, delaying relapse and extending survival. Collectively, these results support the therapeutic potential of WNT inhibitors as a strategy to block the cross-talk between the BM stroma and leukaemic cells and reduce ALL chemoresistance.
    Keywords:  WNT pathway; acute lymphoblastic leukaemia; bone marrow niche; chemoresistance
    DOI:  https://doi.org/10.1111/bjh.70431
  18. Elife. 2026 Mar 23. pii: RP105523. [Epub ahead of print]14
    The cytoplasm of living cells can sustain transient and steady intracellular pressure gradients.
    Majid Malboubi, Mohammad Hadi Esteki, Malti B Vaghela, Lulu I T Korsak, Ryan J Petrie, Emad Moeendarbary, Guillaume Charras.
      Understanding the physical basis of cellular shape change in response to both internal and external mechanical stresses requires characterisation of cytoplasmic rheology. At subsecond time-scales and micron length-scales, cells behave as fluid-filled sponges in which shape changes necessitate intracellular fluid redistribution. However, whether these cytoplasmic poroelastic properties play an important role in cellular mechanical response over length- and time-scales relevant to cell physiology remains unclear. Here, we investigated whether and how a localised deformation of the cell surface gives rise to transient intracellular flows spanning several microns and lasting seconds. Next, we showed that pressure gradients induced in the cytoplasm can be sustained over several minutes. We found that stable pressure gradients can arise from the combination of cortical tension, cytoplasmic poroelasticity, and water flows across the membrane. Overall our data indicate that intracellular cytosolic flows and pressure gradients may play a much greater role than currently appreciated, acting over time- and length-scales relevant to mechanotransduction and cell migration, signifying that poroelastic properties need to be accounted for in models of the cell.
    Keywords:  AFM; cytoplasm; cytoskeleton; human; membrane transport; physics of living systems; poroelasticity; pressure
    DOI:  https://doi.org/10.7554/eLife.105523
  19. Cell Death Dis. 2026 Mar 23.
    Noncanonical role of KDM5C in conferring bortezomib resistance via the PERK‒Nrf2 axis in multiple myeloma.
    Peifen Lu, Wenbin Shangguan, Weiwei Qian, Dongliang Wu, Wenyang Li, Jingjing Huang, Peipei Xu, Dijun Chen, Feng Li, Bing Chen, Quan Zhao.
      Conventionally, KDM5C functions as a specific demethylase that targets histone H3 lysine 4 dimethyl and trimethyl modifications, crucial for gene expression. However, the role of KDM5C in multiple myeloma (MM) progression and bortezomib (BTZ) resistance has remained elusive. In this study, we found noncanonical functions of KDM5C in MM. Specifically, KDM5C binds to CBP and MYC, conferring BTZ resistance in MM through a demethylase-independent mechanism. Our investigations revealed that KDM5C is markedly upregulated in BTZ-resistant MM patients as well as those with relapsed MM. Significantly, the expression level of KDM5C exhibits an inverse correlation with the overall survival of MM patients. Moreover, KDM5C is indispensable for MM cell proliferation. Depletion of KDM5C augmented the sensitivity of MM cells to BTZ treatment both in vitro and in vivo. We found that KDM5C forms a novel complex with CBP and MYC via its PHD2 domain. This complex formation triggers lysine 27 acetylation in histone H3 (H3K27ac) and subsequent enrichment of H3K27ac on the PERK promoter. As a result, PERK transcription is activated, and Nrf2 phosphorylation is promoted, bolstering the unfolded protein response within the endoplasmic reticulum of MM cells. In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.
    DOI:  https://doi.org/10.1038/s41419-026-08591-7
  20. Nat Med. 2026 Mar 24.
    Enhanced dynamic risk stratification of smoldering multiple myeloma.
    Floris Chabrun, Daniel E Schwartz, Susanna Gentile, Elias K Mai, Tulika R Gupta, Jacqueline Perry, David M Cordas Dos Santos, Thomas Hielscher, Annika Werly, Sophia K Schmidt, Foteini Theodorakakou, Despina Fotiou, Christine Ivy Liacos, Nikolaos Kanellias, Noelia Collado Gisbert, Esperanza Martin-Sanchez, Rosalinda Termini, Johannes Waldschmidt, Selina J Chavda, Louise Ainley, Matteo Claudio Da Vià, Claudio De Magistris, Loredana Pettine, Michael A Timonian, Jean-Baptiste Alberge, Vidhi Patel, Patrick Costello, Catherine Tobia, Sally Phan, Jennifer Lamb, Maria-Theresa Silverio, Maya Davis, Elizabeth K O'Donnell, Catherine R Marinac, Omar Nadeem, Niccolo Bolli, Kwee Yong, K Martin Kortüm, Hermann Einsele, María-Victoria Mateos, Shaji Kumar, Jesús F San-Miguel, Bruno Paiva, Efstathios Kastritis, Meletios A Dimopoulos, Marc S Raab, Lorenzo Trippa, Irene M Ghobrial.
      Accurate prediction of risk of progression from smoldering multiple myeloma (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled a cohort of 2,344 patients with SMM from seven international centers with longitudinal clinical and biological data to train and validate the Precursor Asymptomatic Neoplasms by Group Effort Analysis (PANGEA)-SMM risk models. Four evolving biomarkers were significantly associated with shorter time to progression: M-protein increase ≥0.2 g dl-1, involved/uninvolved serum free light chain ratio increase ≥20, creatinine increase >25% and hemoglobin decrease ≥1.5 g dl-1. PANGEA-SMM outperforms established models, including the 20/2/20 and IMWG models, by more accurately predicting progression (C-statistic = 0.79), even without biomarker history (C-statistic = 0.78) or recent bone marrow biopsy (C-statistic = 0.78). We present PANGEA-SMM to the community as an easy-to-use, open-access tool for risk stratification in SMM. Validation tools are available to compare PANGEA-SMM to established models.
    DOI:  https://doi.org/10.1038/s41591-026-04304-x
  21. Haematologica. 2026 Mar 26.
    Disrupting adaptive proteostasis to overcome proteasome inhibitor resistance.
    Annamaria Brioli.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300486
  22. Cell Death Discov. 2026 Mar 23.
    ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances.
    Lisa Ehlers, Marjon Wouters, Bethany Pillay, Selket Delafontaine, Giorgia Bucciol, Marco Baggio, Mariia Dzhus, Anneleen Hombrouck, Alexandra Damerau, Lien De Somer, Rik Schrijvers, Steven Vanderschueren, Maarten Jacquemyn, Tilmann Kallinich, Dirk Daelemans, Bart Ghesquière, Patrizia Agostinis, Leen Moens, Isabelle Meyts.
      Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.
    DOI:  https://doi.org/10.1038/s41420-026-03027-9
  23. J Biol Chem. 2026 Mar 20. pii: S0021-9258(26)00261-9. [Epub ahead of print] 111391
    The RING E3 Ligase RLIM Drives Oxidative Stress-Induced Stem Cell Dysfunction through MDM2-p53 Signaling.
    Xiaoyue Li, Caiqi Shen, Yajie Li, Lijun Wu, Jia Gao, Dong Zhu, Dong Dong, Feifei Chen, Peisheng Jin.
      Chronic diabetic ulcers present a persistent challenge due to delayed wound healing. At the wound site, oxidative stress impairs stem cell survival and differentiation, accelerates senescence, and impairs autophagy. RLIM was identified as a critical regulator in human umbilical cord mesenchymal stem cells (hUCMSCs), where oxidative stress-induced RLIM upregulation leads to MDM2 degradation and stabilization of p53. Functionally, RLIM upregulation under oxidative stress inhibited autophagy, induced cellular senescence, and significantly impaired angiogenesis, cell migration, and immunomodulatory functions, ultimately hindering diabetic wound healing in vivo. These results highlight the RLIM-MDM2-p53 signaling axis as a pivotal pathway governing stem cell senescence and function under oxidative stress, offering promising therapeutic targets to enhance stem cell-based approaches for diabetic wound repair.
    Keywords:  Autophagy; Cellular senescence; Diabetes wound healing; Human umbilical cord mesenchymal stem cells (hUCMSCs); Ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2026.111391
  24. Sci Adv. 2026 Mar 27. 12(13): eaea4059
    A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.
    Nesteene Joy Param, Elisa Arceci, Francesco Fiorentino, Luca Pignata, Denis Torre, Nayeli Gutiérrez-Trejo, Jia Yi Fong, Pierre-Alexis Goy, Brenda Y Han, Chiara Lambona, Elisabetta Di Bello, Carola Castiello, Marco Barone, Megan Schwarz, Cheryl Arrowsmith, Koichi Ito, Peggy Scherle, Dave Keng Boon Wee, Steven Ndoye, Tommaso Tabaglio, Anand D Jeyasekharan, Manikandan Lakshmanan, Roberto Cirilli, Hansjörg Habisch, Tobias Madl, Andrea Mattevi, Sergio Valente, Antonello Mai, Ernesto Guccione.
      Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.
    DOI:  https://doi.org/10.1126/sciadv.aea4059
  25. Cell. 2026 Mar 20. pii: S0092-8674(26)00116-9. [Epub ahead of print]
    The E3-ome gene-centric compendium reveals the human E3 ligase landscape.
    Ngee Kiat Chua, Tania J González-Robles, Cameron J Reddington, Jane Dudley-Fraser, Richard W Birkinshaw, Jiru Han, Ashleigh Solano, Soon Wei Wong, Tomasz Kochańczyk, Joshua J Peter, Mark A Nakasone, Florian Aust, Jacob Munro, Yeh Huei Tong, Julie Iskander, Waruni Abeysekera, Alex Garnham, Hannah Huckstep, Matthew E Ritchie, Ingrid Wertz, Sarah Hymowitz, Sharad Kumar, Ron C Conaway, Gilbert G Privé, Alex N Bullock, Jeffrey J Babon, Rachel E Klevit, Sonja Lorenz, Alessio Ciulli, Eric S Fischer, Nicolas H Thomä, Radosław P Nowak, Brenda A Schulman, Michael Rapé, Katrin Rittinger, Julia K Pagan, Melanie Bahlo, Joel P Mackay, Peter D Mace, Christopher D Lima, Ronald T Hay, David Komander, Bernhard C Lechtenberg, Claudio A P Joazeiro, Michele Pagano, Kay Hofmann, Rebecca Feltham.
      To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.
    DOI:  https://doi.org/10.1016/j.cell.2026.01.029
  26. bioRxiv. 2026 Mar 16. pii: 2026.03.13.711689. [Epub ahead of print]
    Survey of the human proteostasis network: the ubiquitin-proteasome system.
    Suzanne Elsasser, Evan T Powers, Thomas Stoeger, Xiaojing Sui, Roy D Kurtzbard, Patricia Martínez-Botía, Margaret A Wangeline, Alejandro Rodriguez Gama, Edward L Huttlin, Lisa P Elia, Jeffery W Kelly, Jason E Gestwicki, Judith Frydman, Steven Finkbeiner, Eugenia M Clerico, Richard I Morimoto, Miguel A Prado, Alfred C O Vertegaal, Kay Hofmann, Daniel Finley.
      Modification by ubiquitination governs the half-lives of thousands of proteins that are fated for elimination by either the proteasome or autophagy pathways, depending on the intricate architectures of ubiquitin modification. This system mediates quality control for individual proteins, protein complexes, and organelles, as well as myriad purely regulatory functions. Here we provide a comprehensive survey of the ubiquitin-proteasome system (UPS), the scope of which is at present poorly defined. The UPS, with the inclusion of pathways involving ubiquitin-like modifiers, comprises in our estimate over 1400 distinct proteins in humans, a vast set of activities whose collective impact on the biology of the cell is pervasive. The UPS is an integral component of the proteostasis network (PN), the remainder of which we have also surveyed in recent studies. With the addition of molecular chaperones, proteins from autophagy-lysosome pathway, and related activities, the PN includes in total over 3100 components by our estimates. Comprehensive and systematic definition of these pathways should support a range of ongoing investigations in the areas of genomics, proteomics, biochemistry, cell biology, and disease research.
    DOI:  https://doi.org/10.64898/2026.03.13.711689
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