bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–08–16
twenty-one papers selected by
William Grey, University of York
  1. RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
  2. The Fbxw11-Dpysl2 ubiquitin axis restrains the progression of acute myeloid leukemia.
  3. Tgfbr3 is required for the long-term maintenance of self-renewal potential in murine hematopoietic stem cells.
  4. Unlocking the Curative Potential of Gene Transfer and Editing for Hematopoietic Disorders.
  5. Latent effector T cells mediate immunotherapy responses in the bone marrow microenvironment.
  6. DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
  7. TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia.
  8. CD47 promotes myeloma cell growth through JAK-STAT3/MYC signalling and is targetable by ruxolitinib.
  9. Dysregulated NF-κB dynamics impair proteostasis and drive premature differentiation in aging B cell development.
  10. KDM4C inhibition reinforces NK cell cytotoxicity through the cGAS-STING pathway in TP53-mutated AML.
  11. TP53 mutation drives unique transcriptional and functional vulnerabilities independent of del(17p) in multiple myeloma.
  12. USP8 controls proteostasis pathways in B cells and multiple myeloma.
  13. Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.
  14. Prognostic value of measuring LSC frequency in AML: a systematic review and meta-analysis.
  15. FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress myelopoiesis.
  16. Systematic differences in protein stability underlie species-specific developmental tempo.
  17. Multilayer modeling reveals an endogenous retrovirus signature predictive of induction chemotherapy failure in AML.
  18. Mutant p53 reactivation and DNA demethylation in the treatment of AML/MDS.
  19. Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging.
  20. Protocol for isotype-resolved 3D imaging and quantification of bone marrow plasma cells in murine femurs.
  21. Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.
  1. Sci Adv. 2026 Aug 14. 12(33): eaec3399
    RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
    Christopher Mapperley, Elise Georges, Ali A Azar, Yuka Kabayama, Hannah Lawson, Iwo Kucinski, Derek George, Joana Campos, Corey Fyfe, Jozef Durko, Wei Y Chan, Lewis Allen, Babak Jazayeri, Edward Blacker, Louie N van de Lagemaat, Aurelien Tripp, Theodoros I Roumeliotis, Giulia Guiducci, Eleanor Herbert, Jasmin Paris, Jyoti Choudhary, George Poulogiannis, Robert M Campbell, Marcos Morgan, Lovorka Stojic, Folkert J Van Werven, Douglas Vernimmen, Berthold Göttgens, Dónal O'Carroll, Kamil R Kranc.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.
    DOI:  https://doi.org/10.1126/sciadv.aec3399
  2. Cancer Lett. 2026 Aug 12. pii: S0304-3835(26)00546-X. [Epub ahead of print] 218782
    The Fbxw11-Dpysl2 ubiquitin axis restrains the progression of acute myeloid leukemia.
    Lina Wang, Yifei Li, Wanzhen Xie, Ruiyun Li, Xiaoxi Cui, Siqi Zhang, Qian Ren, Guoguang Zheng.
      Ubiquitination regulation is essential for maintaining protein homeostasis. Dysregulated ubiquitination is increasingly recognized to participate in malignant progression. Fbxw11, a substrate-recognition subunit of SCF-type E3 ligases, is involved in tumorigenesis and progression. However, its role and molecular mechanism in acute myeloid leukemia (AML) have not been elucidated. Here we demonstrat that lower levels of Fbxw11 were detected in AML patients and correlated with worse prognosis. Furthermore, overexpression of Fbxw11 delayed AML progression by reducing leukemia stem cell (LSC) frequency and inhibiting leukemia cell migration. Mechanistically‌, quantitative proteomics combined with co-immunoprecipitation and ubiquitination assays identified dihydropyrimidinase-like 2 (Dpysl2) as a direct substrate of Fbxw11, leading to its poly-ubiquitylation and proteasomal degradation. Moreover, overexpression of Dpysl2 reversed the effects of Fbxw11 on LSC levels and migration of AML cells as well as accelerated AML progression in vivo. In addition, inhibition of Dpysl2 with lacosamide, an FDA-approved antiepileptic drug, phenocopied Fbxw11 restoration and delayed AML progression. Lacosamide combined with cytarabine further prolonged the survival of AML mice. Our results suggest Fbxw11 as an intrinsic suppressor in AML progression by regulating the ubiquitination and degradation of Dpysl2, providing new insights into ubiquitination regulation and highlighting the potential of targeting the Fbxw11-Dpysl2 axis as a therapeutic strategy for AML.
    Keywords:  Acute myeloid leukemia; Dpysl2; Fbxw11; Lacosamide; Ubiquitination regulation
    DOI:  https://doi.org/10.1016/j.canlet.2026.218782
  3. Blood Sci. 2026 Sep;8(3): e00307
    Tgfbr3 is required for the long-term maintenance of self-renewal potential in murine hematopoietic stem cells.
    Xialin Li, Qitai Yang, Jinglei Zhai, Xiaobing Zhang, Fang Dong, Hideo Ema.
      Transforming growth factor-β (TGF-β) signaling plays a crucial role in maintaining the quiescence and self-renewal potential of hematopoietic stem cells (HSCs). Despite decades of research, the underlying mechanisms of TGF-β signaling in HSCs remain elusive due to conflicting phenotypes of various knockout (KO) mouse models. Here, we show that HSCs co-express Tgfbr2, Tgfbr3, and Endoglin (Eng) but rarely express Tgfbr1, whereas lymphocytes co-express Tgfbr1 and Tgfbr2 but rarely express Tgfbr3 or Eng. We also demonstrate that Tgfbr3 is dispensable for the maintenance of immune homeostasis, in contrast to Tgfbr1 and Tgfbr2, either of which is essential for lymphocyte homeostasis. Serial transplantation assays revealed that deletion of Tgfbr3 in HSCs had little effect on short-term reconstitution but impaired long-term self-renewal potential, a similar phenotype observed in Eng conditional KO mice. Therefore, we propose that lymphocytes rely on the Tgfbr1/Tgfbr2 complex as suggested by the classical model, whereas HSCs require the unique Tgfbr2/Tgfbr3/Eng complex to orchestrate TGF-β signaling. Collectively, this study reveals Tgfbr3 as a critical regulator in the maintenance of HSC self-renewal potential and suggests a novel TGF-β receptor complex specific to HSCs.
    Keywords:  Endoglin; Hematopoietic stem cells; Quiescence; Transforming growth factor-β; Transforming growth factor-β receptors 1, 2, 3
    DOI:  https://doi.org/10.1097/BS9.0000000000000307
  4. Exp Hematol. 2026 Aug 14. pii: S0301-472X(26)00126-8. [Epub ahead of print] 105493
    Unlocking the Curative Potential of Gene Transfer and Editing for Hematopoietic Disorders.
    Kohei Shiroshita, Anne Stolz, Camille Malouf, Vu L Tran, Jingjing Li, Mitchell J Weiss, Luigi Naldini.
      Hematopoietic stem and progenitor cells (HSPCs) gene therapy may transform the therapeutic landscape for inherited hematological disorders and already offers potentially curative options for some diseases, including inborn errors of immunity and β-hemoglobinopathies. Its continued success relies on further refinement of gene transfer technologies, gene editing tools such as CRISPR-Cas, and optimized ex vivo HSPC manipulation protocols that ensure robust, long-term engraftment and clonal diversity with reduced-toxicity, non-genotoxic conditioning strategies. Here, we review recent developments and refinements in gene transfer and editing technologies for HSPCs, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar. Future directions must prioritize integrating technological innovation with the development of equitable and simplified models to reduce costs and ensure that these life-saving cellular therapies reach patients worldwide. Teaser abstract Hematopoietic stem and progenitor cells (HSPCs) gene therapy is advancing rapidly, with lentiviral gene transfer, genome editing, and emerging in vivo delivery approaches expanding the therapeutic landscape for inherited hematologic disorders. Recent clinical successes have demonstrated the potential for durable correction, while ongoing refinements continue to improve safety, efficacy, and feasibility. Key challenges remain in genotoxicity, conditioning toxicity, manufacturing scalability, and equitable global access.
    Keywords:  Gene therapy; clinical translation; gene editing; hematopoietic stem cells; hemoglobinopathy; lentiviral vectors
    DOI:  https://doi.org/10.1016/j.exphem.2026.105493
  5. Cancer Cell. 2026 Aug 10. pii: S1535-6108(26)00349-1. [Epub ahead of print]
    Latent effector T cells mediate immunotherapy responses in the bone marrow microenvironment.
    Niklas Kehl, Tim R Wagner, Simon Steiger, Tamara Boschert, Michael Kilian, Antonia Schach, Julius J Michel, Kane Foster, Gabrielle M Hernandez, Claudia Ctortecka, Anna D Metzler, Alanna Kirschner, Arne Van der Vreken, Dominik Humer, René Onken, Sven Cuntz, Julian Zoller, Cornelius Funk, Selina Neunhäuser, Maximilian Mönnig, Bruno Schönfelder, Simon Renders, Claudia Maldonado Torres, Lilli S Sester, Jan H Frenking, Franziska Werner, Wolfram Osen, Katharina Lindner, Ezgi Sen, Sabrina Schumacher, Daria Galas-Filipowicz, Evie Fitzsimons, Edward W Green, Patrick Schmidt, John M Lindner, Sebastian Uhrig, Lukas Bunse, Benny Chain, Hartmut Goldschmidt, Niels Weinhold, Stefan Fröhling, Tim Sauer, Simon Raffel, Jennifer G Abelin, Steven A Carr, Kwee Yong, Andreas Trumpp, Carsten Müller-Tidow, Karsten Rippe, Marc S Raab, Michael Platten, Stefan B Eichmüller, Mirco J Friedrich.
      T cell-mediated immune surveillance is critical for cancer control, yet its role in bone marrow malignancies remains poorly understood. Here, we integrate TCR profiling, HLA immunopeptidomics, and functional screening to characterize tumor-reactive T cells in the bone marrow of patients with multiple myeloma (MM) and acute myeloid leukemia (AML). These cells are transcriptionally defined by a conserved effector program distinct from the exhausted phenotype of tumor-reactive T cells in solid cancers. Immunopeptidomic profiling reveals a partially shared antigen landscape enriched for noncanonical peptides driving convergent TCR responses. We develop TFiT (tumor-reactive features in T cells), a transcriptional classifier that identifies these cells and stratifies immunotherapy, but not chemotherapy, response across independent MM and AML cohorts, supporting its specificity for T cell-mediated tumor control. These findings reveal a latent but activatable anti-tumor T cell compartment in bone marrow malignancies and provide a framework for engaging endogenous immunity in MM and AML.
    Keywords:  TCR repertoire; TFiT; acute myeloid leukemia; bispecific antibodies; bone marrow microenvironment; immune biomarker; immunopeptidomics; multiple myeloma; noncanonical antigens; tumor-reactive T cells
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.011
  6. Blood. 2026 Aug 03. pii: blood.2025030349. [Epub ahead of print]
    DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
    Maria Eugenia Gallo Cantafio, Noemi Puccio, Roberta Torcasio, Ilenia Valentino, Ludovica Ganino, Yuanyuan Jin, Anil Aktas Samur, Pierpaolo Murfone, Alessia Gallo, Mehmet K Samur, Nicola Cuscino, Cesarina Giallongo, Ida Daniela Perrotta, Alessia Ciarrocchi, Federico Tallarigo, Ernestina Marianna De Francesco, Davide Barbuto, Ross David Jansen-van Vuuren, Luka Jedlovčnik, Danchen Wu, Enrica Antonia Martino, Daniele Tibullo, Francesco Di Raimondo, Massimo Gentile, Antonino Neri, Stephen L Archer, Eugenio Morelli, Nikhil C Munshi, Giuseppe Viglietto, Mariateresa Fulciniti, Nicola Amodio.
      Mitochondrial dynamics is a key regulator of cellular homeostasis, orchestrating metabolic reprogramming that fuels tumor progression and treatment resistance. In multiple myeloma (MM), however, the functional relevance of mitochondrial remodeling has not been fully defined. Using ultrastructural analyses, we reveal that MM cells display a highly fragmented mitochondrial network, a phenotype further exacerbated in both cell lines and primary MM cells resistant to proteasome inhibitors. Transcriptomic profiling across multiple patient-derived datasets consistently demonstrated upregulation of DNM1L gene, which encodes the mitochondrial fission GTPase DRP1, particularly in relapsed and refractory MM, and revealed a significant association with inferior overall survival. Disrupting mitochondrial fission, either through genetic targeting of DNM1L or pharmacologic inhibition of DRP1 with the selective small molecule inhibitor Drpitor1a, resulted in pronounced mitochondrial dysfunction, impaired oxidative phosphorylation, and potent anti-myeloma activity in vitro, culminating in a hybrid cell death program with a predominant apoptotic component accompanied by ferroptotic features. These effects were recapitulated in vivo in a bortezomib-resistant xenograft model, where either DNM1L depletion or DRP1 inhibition produced similar outcomes. Mechanistically, the transcription factor c-MYC upregulated DNM1L expression, and DRP1-dependent mitochondrial fragmentation sustained MYC-driven oxidative metabolism and lipid synthesis. Altogether, these findings establish aberrant mitochondrial fission as a pathogenic hallmark of MM and highlight DRP1 inhibition as a promising therapeutic approach, especially for relapsed or refractory disease.
    DOI:  https://doi.org/10.1182/blood.2025030349
  7. Nat Cancer. 2026 Aug 12.
    TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia.
    Qiwei Wang, Jingyi Li, Xin Zeng, Lina Liu, Huan Lu, Yin Zhao, Yan Huang, Rui Wang, Chen Wang, Yingli Han, Yishan Ye, Yanmin Zhao, Jimin Shi, Yi Luo, Weiyan Zheng, Yongxian Hu, Shibing Wang, Xiangmin Tong, He Huang, Shanshan Pei, Pengxu Qian.
      Acute myeloid leukemia (AML) remains challenging, especially for older or unfit individuals who develop resistance to venetoclax (VEN)-based regimens. Although TIM3 represents a promising AML target, clinical blockade has yielded suboptimal outcomes. Here, we develop VINCENT (VEN-integrated natural killer cell engager targeting TIM3), a therapeutic platform combining anti-CD16 and anti-TIM3 antibodies with nanoformulated VEN. In VEN-resistant AML cell lines and patient-derived xenograft models, VINCENT overcomes resistance by enhancing VEN delivery, eliminating TIM3+ blasts and dysfunctional T cells and activating natural killer (NK) cells. In primary AML samples, VINCENT selectively kills drug-resistant blasts, with efficacy correlating with the NK cell-to-TIM3+ blast ratio. Single-cell transcriptomics reveals VINCENT depletes high-TIM3 blasts and remodels the immunosuppressive microenvironment toward immune competence. Collectively, VINCENT simultaneously addresses VEN resistance, NK cell dysfunction and immune evasion, offering a personalized option for elderly or unfit individuals with AML failing standard VEN regimens.
    DOI:  https://doi.org/10.1038/s43018-026-01217-z
  8. Br J Haematol. 2026 Aug 14.
    CD47 promotes myeloma cell growth through JAK-STAT3/MYC signalling and is targetable by ruxolitinib.
    Omar Faruq, Deepak Iyer, Patrick Wang, Mariusz Shrestha, Cuihong Wei, Aaron D Schimmer, Hong Chang.
      Cluster of differentiation 47 (CD47), a 'don't eat me' immune checkpoint receptor, is frequently overexpressed on multiple myeloma (MM) cells and contributes to immune evasion. While its immune regulatory function is well established, the intrinsic oncogenic role of CD47 remains poorly understood. Here, we demonstrate for the first time that CD47 intrinsically promotes myeloma cell proliferation and survival by activating the JAK/STAT3-MYC (Janus kinase/signal transducer and activator of transcription 3 - MYC) signalling axis. CD47 overexpression increased cell growth, accelerated G1-M-cell cycle progression and promoted anchorage-independent colony formation, accompanied by elevated phosphorylation of STAT3 and upregulation of MYC, whereas CD47 knockdown produced the opposite effects. Transcriptomic analysis of patient datasets revealed that high CD47 expression was associated with enrichment of the JAK-STAT3 and MYC pathways, and CD47 levels positively correlated with STAT3 and MYC expression, suggesting a potential regulatory interplay among these molecules. Pharmacological inhibition using the JAK1/2 inhibitor ruxolitinib (Rux) decreased cell viability, induced apoptosis and suppressed STAT3 and MYC signalling. Moreover, Rux synergized with bortezomib in myeloma cell lines and primary patient samples but spared normal cells. Collectively, these findings identify CD47 as an oncogenic driver with an intrinsic signalling function in MM and highlight the CD47-STAT3-MYC axis as a promising therapeutic target.
    Keywords:  CD47; STAT3; c‐MYC; multiple myeloma (MM); ruxolitinib (Rux)
    DOI:  https://doi.org/10.1111/bjh.70736
  9. Cell Press Blue. 2026 Jun 15. pii: 100051. [Epub ahead of print]1(3):
    Dysregulated NF-κB dynamics impair proteostasis and drive premature differentiation in aging B cell development.
    Yu-Sheng Lin, Valentina Alonso, Apeksha Singh, Yi Liu, Ying Tang, Arnav Mehta, Jennifer K King, May Paing, Nathan Salomonis, H Leighton Grimes, Jennifer J Chia, Dinesh S Rao, Alexander Hoffmann.
      Aging and inflammation reduce bone marrow B cell output. While myeloid bias among multi-potent progenitors is one cause, how the developmental cascade of B-committed progenitors is affected remains less well characterized. Here, we identify dynamic modulation of the inflammation response factor NF-κB as a hallmark of healthy lymphopoiesis, but it is diminished in aged B-lymphopenic mice. Indeed, genetic dysregulation of NF-κB dynamics results in severe B-lymphopenia. Model-aided analysis of in vivo progenitor populations and ex vivo experimental time courses reveals that accelerated differentiation of pro-B cells results in skipping critical proliferative phases. Single-cell transcriptomics confirmed premature cell-state transitions, characterized by inappropriate activation of NF-κB target genes that cause wholesale increases in protein synthesis rates. This imbalanced proteostasis leaves little spare energetic capacity to support population expansion, leading to premature differentiation. Our findings indicate that developmental NF-κB dynamics safeguard B lymphopoiesis, thereby identifying a mechanistic cause of age-associated humoral immune deficiency.
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100051
  10. Aging Dis. 2026 Aug 09.
    KDM4C inhibition reinforces NK cell cytotoxicity through the cGAS-STING pathway in TP53-mutated AML.
    Xinyi Zhang, Huilan Liu, Liangquan Geng, Panpan Huang, Mengqing Gao, Qian Fan, Kaishuang Jiang, Na Zhao, Xuxu Zhao, Huaiping Zhu, Cihangir Duy, Haiming Wei, Dongyao Wang.
      TP53-mutated acute myeloid leukemia (AML) is associated with an extremely poor prognosis and is refractory to conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We identified high expression of lysine demethylase 4C (KDM4C) in AML, particularly in TP53-mutated AML. Pharmacological inhibition of KDM4C with QC6352 predominantly induced apoptosis in TP53-wild-type AML cells, whereas it caused limited apoptosis but pronounced senescence and growth arrest in TP53-mutated AML cells. In TP53-mutated AML cells, QC6352 induced senescence-associated cytosolic DNA accumulation and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to the upregulation of NK cell-activating ligands and enhancing NK cell-mediated cytotoxicity. In vivo, QC6352 effectively attenuated AML progression, and its combination with NK cell therapy further reduced leukemic burden and prolonged survival in mice. Collectively, these findings demonstrate that pharmacological KDM4C inhibition with QC6352 induces cellular senescence and enhances the intrinsic immunogenicity of TP53-mutated AML cells through activation of the cGAS-STING pathway. The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT.
    DOI:  https://doi.org/10.14336/AD.2026.0432
  11. iScience. 2026 Aug 21. 29(8): 116932
    TP53 mutation drives unique transcriptional and functional vulnerabilities independent of del(17p) in multiple myeloma.
    Dimitrios Tsallos, Nemo Ikonen, Juho J Miettinen, Muntasir Mamun Majumder, Samuli Eldfors, Imre Västrik, Alun Parsons, Minna Suvela, Katie Dunphy, Paul Dowling, Despina Bazou, Peter O'Gorman, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Caroline A Heckman.
      TP53 abnormalities contribute to treatment resistance and poor prognosis in multiple myeloma (MM), yet their functional consequences remain unclear. Here, we integrate ex vivo drug sensitivity profiling, genomics, transcriptomics, and proteomics across 167 CD138+ bone marrow patient samples to characterize TP53-associated vulnerabilities. Genome-wide CRISPR-Cas9 and RNAi screening identify vulnerabilities in TP53-mutated MM, with or without del(17p), highlighting the dependency on spindle organization, mitotic regulation, DNA synthesis, and transcriptional and metabolic regulation, but independence from MDM2. CD138+ cells with TP53 mutation exhibit increased sensitivity to chemotherapeutics, HDAC, HSP90, IGF1R, and PI3K/AKT/mTOR inhibitors as well as RNA synthesis inhibitor plicamycin, with distinct drug response profiles of MM with del(17p) and WT TP53. Our study provides new insights into refining TP53 classification to optimize treatment strategies for high-risk MM.
    Keywords:  del(17p); drug sensitivity; high-risk genetic abnormalities; multi-omic profiling; multiple myeloma; precision oncology; therapeutic vulnerabilities; tp53 mutation
    DOI:  https://doi.org/10.1016/j.isci.2026.116932
  12. Leukemia. 2026 Aug 11.
    USP8 controls proteostasis pathways in B cells and multiple myeloma.
    Almut Dufner, Fabien Thery, Gianni Monaco, Jelena Lazarevic, Oliver Gorka, Nina Chevalier, Marta Campos Alonso, Maximilian Frosch, Gerbrand J van der Heden van Noort, Kira Allmeroth, Marco Prinz, Olaf Groß, Huib Ovaa, Paul P Geurink, Wolfgang W Schamel, Martin S Denzel, Vigo Heissmeyer, Benedikt Jacobs, Mirle Schemionek, Francis Impens, Heiko Bruns, Klaus-Peter Knobeloch.
      Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
    DOI:  https://doi.org/10.1038/s41375-026-03086-y
  13. Blood. 2026 Aug 04. pii: blood.2026033417. [Epub ahead of print]
    Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.
    Meher Bolisetti Gayatri, Bei Jia, Anthony J Veltri, Vysakh Anandan, Maoshuo Yang, Jing Li, Kenneth Man Hei Chan, Sophie Verbeke, Jiangchen Yao, Sarah E Granozio, Yun Jiang, Esra'a Keewan, Jacqueline Ann Cook, Xiaolan Zhu, Erik A Ranheim, Zhe Wang, Chih-Hsing Chou, Kalyan V Nadiminti, H Leighton Grimes, Marulasiddappa Suresh, Hong Zheng, Xiaona You, Jing Zhang.
      Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ~30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug re-purpose screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS;ASXL1-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T cell co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.
    DOI:  https://doi.org/10.1182/blood.2026033417
  14. Blood Adv. 2026 Aug 14. pii: bloodadvances.2026021094. [Epub ahead of print]
    Prognostic value of measuring LSC frequency in AML: a systematic review and meta-analysis.
    Tom Reuvekamp, Marry Lin, Lok Lam Ngai, Kasper J Croese, Kirsten A Ziesemer, Mitra Nekouei Shahraki, Vera M R von Pickartz, Lukas H Haaksma, Arjan A van de Loosdrecht, Sylvie D Freeman, David C de Leeuw, Jacqueline Cloos.
      Leukemia stem cells (LSC) are thought to be responsible for relapse in patient with acute myeloid leukemia (AML). LSC can be quantified at diagnosis to improve risk stratification, and during follow-up to monitor residual disease. To systematically evaluate the prognostic relevance of measuring LSC at diagnosis and in remission in patients with AML, we conducted a systematic and reconstructed individual patient data meta-analysis. We performed a comprehensive search for studies that reported overall survival (OS) and/or event-free survival (EFS) in relation to LSC measurements at diagnosis or in remission. We reconstructed individual patient data based on Kaplan Meier curves. Fifty-six studies were included, including a total of 44 cohorts (n=7781) for OS and 37 cohorts (n=5032) for EFS at diagnosis, and 19 cohorts (n=2006) for OS and 22 cohorts (n=1342) for EFS in remission. Positive LSC status was significantly associated with inferior OS and EFS at diagnosis (OS: hazard ratio [HR] 1.96 (1.85-2.08); EFS: HR 2.32 (2.15-2.49)) and in remission (OS: HR 2.59 (2.23-3.03); EFS: HR 2.53 (2.18-2.94)). To conclude, we found that measuring LSC has prognostic relevance both at diagnosis and in remission. This supports LSC frequency as a key prognostic factor that warrants implementation into clinical practice.
    DOI:  https://doi.org/10.1182/bloodadvances.2026021094
  15. Blood. 2026 Aug 10. pii: blood.2026034274. [Epub ahead of print]
    FERMT3 alternative splicing enhances kindlin-3 membrane recruitment for neutrophil adhesion during stress myelopoiesis.
    Serena Lee, Gulinare Halimu, Madeleine Sophie Vidal, Xiaojia Song, Neil J Ball, Klaus Ley, Benjamin T Goult, Lai Wen.
      Leukocyte Adhesion Deficiency syndrome type III (LAD-III) is characterized by recurrent infections and is caused by FERMT3 gene mutations. FERMT3 encodes two isoforms, a standard kindlin-3 and a longer splicing variant, which differs by the addition of four residues Ile-Pro-Arg-Arg (IPRR) in the pleckstrin homology (PH) domain (kindlin-3-IPRR). Previous studies suggested that kindlin-3-IPRR was dysfunctional in inducing neutrophil adhesion, attributed to altered phospholipid binding of the IPRR-containing PH domain. Here we show that kindlin-3-IPRR is fully functional in activating β2 integrins and promotes neutrophil adhesion. The IPRR insert enhances phospholipid binding in vitro and promotes association of kindlin-3 with the plasma membrane. By analyzing RNA sequencing datasets of neutropoiesis, we show that the kindlin-3 short isoform lacking IPRR is highly expressed in neutrophil precursors but downregulated in mature neutrophils. In contrast, a higher proportion of the long isoform was detected in hematopoietic stem cells (HSCs) and mature neutrophils. Kindlin-3-IPRR supports robust adhesion of HSCs. We propose that kindlin-3-IPRR may be crucial in conditions requiring rapid neutrophil mobilization. Indeed, kindlin-3 splicing is altered in neutrophils from patients undergoing stress myelopoiesis after exposure to granulocyte colony-stimulating factor (G-CSF) or HSC transplantation (HSC-T) compared with healthy donors. During stress myelopoiesis induced by G-CSF treatment, the kindlin-3 long isoform is selectively upregulated in mature neutrophils, coinciding with enhanced β2 integrin activation. These findings support a model in which alternative splicing of FERMT3 dynamically fine-tunes integrin activation and leukocyte adhesion during hematopoietic stress, with potential implications for monitoring hematopoietic recovery after HSC transplantation.
    DOI:  https://doi.org/10.1182/blood.2026034274
  16. Dev Cell. 2026 Aug 13. pii: S1534-5807(26)00281-9. [Epub ahead of print]
    Systematic differences in protein stability underlie species-specific developmental tempo.
    Mitsuhiro Matsuda, Henrik M Hammarén, Jorge Lázaro, Mikhail M Savitski, Miki Ebisuya.
      Human embryonic development proceeds more slowly than in mice. The segmentation clock offers a tractable model for studying species-specific developmental tempo, as its oscillation period in human induced presomitic mesoderm (iPSM) cells is approximately twice that of mouse. While the core clock gene HES7 exhibits slower protein degradation in human cells, it remains unclear whether such cross-species differences in protein stability reflect a general principle. Here, we perform a dynamic stable isotope labeling of amino acids in cell culture (SILAC)-based proteomic analysis of ∼5,000 proteins in human and mouse iPSM, and we uncover a broad trend of slower protein degradation in human cells, regardless of subcellular localization or degradation pathways. Moreover, inhibition of glycolysis in mouse iPSM partially phenocopies the human protein stability profile, and modulation of protein stability alters the tempo of both the segmentation clock and cellular differentiation. Our findings establish protein stability, with systematic differences across species, as a key mediator linking metabolism to developmental tempo.
    Keywords:  SILAC proteomics; allochrony; cross-species comparison; developmental tempo; metabolism; protein stability; segmentation clock
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.012
  17. Blood Neoplasia. 2026 Aug;3(3): 100263
    Multilayer modeling reveals an endogenous retrovirus signature predictive of induction chemotherapy failure in AML.
    Nogayhan Seymen, Sila Gerlevik, I Richard Thompson, Merilyn M Albuquerque, Anastasia Conti, Chi Wai Eric So, Mohammad M Karimi.
      
    DOI:  https://doi.org/10.1016/j.bneo.2026.100263
  18. Sci Transl Med. 2026 Aug 12. 18(862): eads9325
    Mutant p53 reactivation and DNA demethylation in the treatment of AML/MDS.
    Huaxin Song, Xinjie Chen, Shujun Xiao, Jiaqi Wu, Yuting Dai, Wen Wu, Yu Wu, Xiangqin Weng, Jiachun Song, Ni Yan, Chenjing Ye, Fangfang Shi, Jingyi Cui, Derun Zheng, Hesong Zhang, Kai Tan, Xueqin Chen, Sujiang Zhang, Jiale Wu, Min Lu.
      Acute myeloid leukemia/myelodysplastic syndromes (AML/MDSs) carrying p53 mutations are refractory to various standard therapies. Arsenic trioxide (ATO) may be effective in restoring function to p53 structural mutants. Here, we report that mutant p53 rescued by ATO treatment strengthened interferon responses triggered by the DNA hypomethylating agent decitabine by transactivating interferon regulatory factor 7 (IRF7) directly. Decitabine also increased the transactivation activity of ATO-rescued mutant p53 by inducing p53-serine-20 phosphorylation and blocking p53-inhibitory mouse double minute 2 homolog (MDM2). ATO and decitabine together killed p53-mutant AML cells and suppressed tumor growth in cell line-derived xenografts. In a first-in-human pilot clinical trial for testing the combination of ATO and decitabine (PANDA-T0 trial, NCT03855371), which enrolled five patients with AML/MDS harboring p53 structural mutations, the ATO and decitabine regimen produced manageable adverse events, and four of the five treated patients achieved complete remission at the level of the bone marrow, associated with p53 activation and interferon response. In 103 p53-mutant patients whose samples were deposited in Ruijin AML/MDS sample repository, 48 distinct p53 missense mutants were identified, 21 of which were classified as ATO and decitabine regimen applicable because of their competencies in activating p53 and interferon responses upon cotreatment. This study establishes an alternative treatment regimen for patients with p53-mutant AML/MDS and provides a proof-of-concept framework for p53-targeted therapy that differentiates between p53 mutations.
    DOI:  https://doi.org/10.1126/scitranslmed.ads9325
  19. Nat Aging. 2026 Aug 10.
    Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging.
    Maziar Divangahi, Katherine Y King.
      
    DOI:  https://doi.org/10.1038/s43587-026-01197-w
  20. STAR Protoc. 2026 Aug 10. pii: S2666-1667(26)00428-4. [Epub ahead of print]7(3): 104775
    Protocol for isotype-resolved 3D imaging and quantification of bone marrow plasma cells in murine femurs.
    Abdouramane Camara, Baizhi Chen, An Qi Xu, Dinis Pedro Calado.
      Bone marrow plasma cells maintain durable antibody responses, but their tissue localization and morphology are difficult to quantify in situ. Here, we present a protocol for isotype-resolved 3D imaging and quantification of bone marrow plasma cells in murine femurs. We describe steps for fixation, optimal cutting temperature (OCT) coumpound embedding, longitudinal opening of mouse femurs, whole-mount immunostaining, optical clearing, and confocal 2D/3D imaging. We detail an Imaris-based workflow for reproducible single-cell segmentation, isotype-resolved counting, and the extraction of morphological features from defined regions of interest.
    Keywords:  Cell Biology; Immunology; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2026.104775
  21. Nat Cell Biol. 2026 Aug;28(8): 1715-1727
    Targeting oncogenic FLT3 uncovers a ferroptosis vulnerability through selenocysteine recoding in acute myeloid leukaemia.
    Minhua Li, Yudan Zhu, Yuki Kageyama, Ken Furudate, Ayumi Kitano, Taotao Tan, Mengdie Feng, Jing Zhou, Tao Wang, Robert J Taylor, Alexandra M Stevens, Md Abul Hassan Samee, Jeffrey A Magee, Koichi Takahashi, Daisuke Nakada.
      Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for therapy-resistant cancers. Glutathione peroxidase 4 and the selenoprotein biosynthesis pathway essential for its translation are key regulators of ferroptosis but lack effective therapeutic targeting. In a drug screening using a selenoprotein translation reporter, here we identify FMS-like tyrosine kinase 3 (FLT3) inhibitors as suppressors of selenoprotein translation that induce ferroptosis in FLT3-mutant acute myeloid leukaemia. Mechanistically, FLT3 inhibition disrupts selenocysteine recoding, in which a UGA stop codon is recoded as selenocysteine via the SECIS element and associated binding proteins. Notably, the antileukemic efficacy of the FLT3 inhibitor gilteritinib was markedly reduced by dietary vitamin E, which attenuated ferroptosis. This study highlights ferroptosis as a vulnerability in FLT3-mutant acute myeloid leukaemia and suggests that high vitamin E intake may compromise tyrosine kinase inhibitor efficacy partly by suppressing ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-026-02016-5
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