bims-scepro 2025-08-10 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–08–10
nineteen papers selected by
William Grey, University of York

Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.
Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice.
Jab1 promotes immune evasion and progression in acute myeloid leukemia models under oxidative stress.
Design of soluble Notch agonists that drive T cell development and boost immunity.
Murine hematopoietic progenitor cell lines with erythroid and megakaryocyte potential.
Single-cell transcriptome profiling reveals blast cell heterogeneity and identifies novel therapeutic target IKZF2 in t(8;21) acute myeloid leukaemia.
CD138 and APRIL regulate plasma cell survival, competition, and retention in the bone marrow niche.
Overexpression of the signaling-coordinator GAB2 can play an important role in Acute Myeloid Leukemia progression.
scplainer: using linear models to understand mass spectrometry-based single-cell proteomics data.
Ultra-high-scale cytometry-based cellular interaction mapping.
The histone-methyltransferase DOT1L cooperates with LSD1 to control cell division in blast-phase MPN.
Dynamics of Ribosomal RNA Transcription and Abundance in Normal and Leukemic Hematopoiesis.
Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells.
Post-Translational Modifications Remodel Proteome-Wide Ligandability.
The RNA-binding protein CELF1 targets ATG5 to regulate autophagy and promote drug resistance in acute myeloid leukemia.
TRIM10β upregulation promotes microtubule destabilization and triggers proteotoxic stress.
Bridging the marrow: a co-culture-platform of leukemia cells and MS5-derived stromal cells or adipocytes.
Precision oncology to overcome resistance in R/R AML in children and adults requires combinations of cytotoxic, targeted, and immunological treatments.
Cell surface crowding is a tunable energetic barrier to cell-cell fusion.

Sci Transl Med. 2025 Aug 06. 17(810): eadn5400

Activation of a nongenetic AHR-ELMSAN1 axis optimizes BET-targeting therapy and suppresses leukemia stem cells in preclinical models.

Xinyue Zhou, Steven Moreira, Cecilia Restelli, Hong Wang, Soheil Jahangiri, Sajesan Aryal, Emily Tsao, Pengcheng Zhang, Mingming Niu, Harish Kumar, Zaldy Balde, Ana Vujovic, Lina Liu, Nicholas Wong, Andrea Arruda, Mark D Minden, Yang Zhou, Bhatia Ravi, Jun Qi, Chunliang Li, Kristin J Hope, Rui Lu.

Developing strategies to enhance the response to bromodomain and extraterminal domain (BET) inhibitors and effectively eradicate cancer stem cells would represent a major cancer treatment advance against leukemia. Through a functional CRISPR screen, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, as a critical regulator of MYC expression and BET inhibitor sensitivity in human acute myeloid leukemia (AML). Constitutive or pharmacological activation of AHR repressed MYC and synergized with BET inhibitors to inhibit MYC transcription and suppress leukemia growth across diverse AML models. Mechanistically, AHR directly up-regulated a noncanonical target, ELMSAN1, a component of the MiDAC histone deacetylase complex, which promotes histone deacetylation at MYC regulatory elements. ELMSAN1 depletion led to up-regulation of MYC and impaired AHR signaling-induced BET inhibitor sensitization. In vivo, AHR agonists enhanced BET inhibitor efficacy in patient-derived xenografts and murine leukemia models, enabling the use of lower BET inhibitor doses while preserving therapeutic benefit and reducing toxicity. This combination suppressed leukemia stem cell (LSC) gene signatures and reduced LSC frequency, with minimal impact on normal hematopoietic stem and progenitor cells in both human cord blood xenografts and immunocompetent mouse models. Together, these findings uncover a MYC-repressive, nongenetic AHR-ELMSAN1 axis that enhances BET-targeting therapies and selectively impairs LSCs, providing a compelling rationale for clinical translation in AML and potentially other MYC-driven cancers.

DOI: https://doi.org/10.1126/scitranslmed.adn5400
J Clin Invest. 2025 Jul 29. pii: e188140. [Epub ahead of print]

Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice.

Sahitya Saka, Zhanping Lu, Yinghua Wang, Peng Liu, Deependra K Singh, Junki P Lee, Carmen G Palii, Tyler R Alvarez, Anna L F V Assumpção, Xiaona You, Jing Zhang, Marjorie Brand, Michael L Atchison, Xuan Pan.

  The fetal liver is the primary site of hematopoietic stem cell (HSC) generation during embryonic development. However, the molecular mechanisms governing the transition of hematopoiesis from the fetal liver to the bone marrow (BM) remain incompletely understood. Here, we identify the mammalian Polycomb group (PcG) protein Yin Yang 1 (YY1) as a key regulator of this developmental transition. Conditional deletion of Yy1 in the hematopoietic system during fetal development results in neonatal lethality and depletion of the fetal HSC pool. YY1-deficient fetal HSCs exhibit impaired migration and fail to engraft in the adult BM, thereby losing their ability to reconstitute hematopoiesis. Transcriptomic analysis reveals that Yy1 knockout disrupts genetic networks controlling cell motility and adhesion in fetal hematopoietic stem and progenitor cells (HSPCs). Notably, YY1 does not directly bind the promoters of most dysregulated genes. Instead, it modulates chromatin accessibility at regulatory loci, orchestrating broader epigenetic programs essential for HSPC migration and adhesion. Together, these findings establish YY1 as a critical epigenetic regulator of fetal HSC function and provide a mechanistic framework to further decipher how temporal epigenomic configurations determine HSC fetal-to-adult transition during development.

Keywords:  Development; Embryonic development; Hematology; Hematopoietic stem cells

DOI:  https://doi.org/10.1172/JCI188140
J Clin Invest. 2025 Aug 05. pii: e183761. [Epub ahead of print]

Jab1 promotes immune evasion and progression in acute myeloid leukemia models under oxidative stress.

Nan Zhang, Qian Wang, Guopeng Chen, Li Liu, Zhiying Wang, Linlu Ma, Yuxing Liang, Jinxian Wu, Xinqi Li, Xiaoyan Liu, Fuling Zhou.

  Acute myeloid leukemia (AML) is the most common hematological malignancy. Leukemia stem cells exhibit high levels of oxidative stress, with reactive oxygen species (ROS) being the primary products of this stress, inducing the expression of Jab1. Previous studies have demonstrated that Jab1, as a transcriptional coactivator of c-JUN, promotes the malignant progression of AML under oxidative stress. However, its role in immune evasion is still under investigation. Here, we observed that knocking out Jab1 reduced the expression of immune checkpoints in vivo, effectively overcame the immune evasion of AML. Interestingly, the deletion of Jab1 had no impact on the maturation of normal hematopoietic cells in mice. Mechanistically, Jab1 directly activated IGF2BP3 by driving the transcription factor c-JUN, consequently modulated the m6A modification of LILRB4 mRNA and promoted immune evasion in AML. Finally, CSN5i-3 effectively disrupted the signaling pathway mediated by Jab1, thereby restoring cellular immune surveillance and halting the progression of AML. Thus, our results highlight the functional role of Jab1 in supporting AML survival and support the development of targeted therapeutic strategies.

Keywords:  Cancer gene therapy; Cell biology; Hematology; Leukemias; Signal transduction

DOI:  https://doi.org/10.1172/JCI183761
Cell. 2025 Jul 29. pii: S0092-8674(25)00798-6. [Epub ahead of print]

Design of soluble Notch agonists that drive T cell development and boost immunity.

Rubul Mout, Ran Jing, Mayuri Tanaka-Yano, Emily D Egan, Helen Eisenach, Martin A Kononov, Roland Windisch, Mohamad Ali Toufic Najia, Allison Tompkins, Luca Hensch, Trevor Bingham, Rajesh Gunage, Yunliang Zhao, Natasha I Edman, Christopher Li, Dahai Wang, Thorsten M Schlaeger, Leonard I Zon, Trista E North, Urban Lendahl, R Grant Rowe, David Baker, Stephen C Blacklow, George Q Daley.

  The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.

Keywords:  Notch signaling; T cell development; T cell immunity; computational protein design; iPSC-derived T cells; immunotherapy; protein agonist; soluble Notch activation; vaccine

DOI:  https://doi.org/10.1016/j.cell.2025.07.009
Nat Commun. 2025 Aug 07. 16(1): 7283

Murine hematopoietic progenitor cell lines with erythroid and megakaryocyte potential.

Ruiqiong Wu, Faraz Salehi, Vanessa Redecke, Zhijun Ma, Marco Marchetti, David Finkelstein, Peng Xu, Yong Cheng, Kimberly A Queisser, Aaron C Petrey, Conroy O Field, Hyun Sook Ahn, Mortimer Poncz, Mitchell J Weiss, Hans Häcker.

Red blood cells and platelets derive from bi-potential bone marrow megakaryocyte-erythroid progenitors, but their study is constrained by cell scarcity and limited experimental systems. Here we show that conditional expression of a virally transduced, regulated form of Hoxa7 enables expansion of murine cells resembling megakaryocyte-erythroid progenitors (Hoxa7-TPO), which undergo erythro-megakaryocytic differentiation upon Hoxa7 inactivation. The close relationship of Hoxa7-TPO cells to megakaryocyte-erythroid progenitors is supported by genetic and phenotypic analyses, and mature Hoxa7-TPO-derived red blood cells and platelets are largely indistinguishable from their primary counterparts. Genetic knock-out studies in Hoxa7-TPO cells recapitulate the key function of Klf1 and Nfe2 in red blood cell and platelet development, respectively, while disruption of the von Willebrand receptor gene Gp1ba recapitulates features of human Bernard-Soulier syndrome. Hence, we developed a versatile experimental system for expansion and differentiation of megakaryocyte-erythroid progenitors to study red blood cell and platelet development and model human diseases.

DOI: https://doi.org/10.1038/s41467-025-62668-z
Br J Haematol. 2025 Aug 08.

Single-cell transcriptome profiling reveals blast cell heterogeneity and identifies novel therapeutic target IKZF2 in t(8;21) acute myeloid leukaemia.

Yu Liu, Wenbing Liu, Yihan Mei, Qianqian Huang, Xiaoyu Liu, Chengcai Guo, Manling Chen, Junli Mou, Shangshang Wang, Wanqing Xie, Zheng Tian, Kejing Tang, Haiyan Xing, Ying Wang, Hui Wei, Runxia Gu, Qing Rao, Min Wang, Shaowei Qiu, Jianxiang Wang.

  The t(8;21)(q22;q22) translocation is one of the most recurrent cytogenetic aberrations in acute myeloid leukaemia (AML). While most patients achieve complete remission, approximately 40% of them still relapse. Early identification and elimination of leukaemia clones with relapse potential could improve prognosis for t(8;21) AML patients. Here, through single-cell RNA sequencing, we characterized the intra-tumoral heterogeneity of t(8;21) AML and identified haematopoietic stem cell (HSC)-like subset as the most quiescent and primitive subgroup among all leukaemia cell populations. Further investigations revealed IKZF2 as the master regulator for HSC-like subset. Notably, IKZF2 was upregulated in t(8;21) AML compared with other AML subtypes and was specifically targeted by AML1-ETO. Using primary samples and mouse models, we verified the high enrichment of IKZF2 in primitive and quiescent leukaemic cells. Moreover, IKZF2 knockout hindered the accumulation of aberrant stem cells driven by AML1-ETO and promoted cellular differentiation both in vitro and in vivo. These facilitate a better understanding of the leukaemia cell heterogeneity in t(8;21) AML and unveil IKZF2 as a potential target for improving current treatment strategies.

Keywords:  HSC‐like subset; IKZF2; t(8;21) AML

DOI:  https://doi.org/10.1111/bjh.70077
Cell Rep. 2025 Aug 05. pii: S2211-1247(25)00894-0. [Epub ahead of print]44(8): 116123

CD138 and APRIL regulate plasma cell survival, competition, and retention in the bone marrow niche.

Rosa Park, Zachary Benet, Zhixin Jing, Jennifer Enright, David R Fooksman.

  Durable serological protection is maintained through the persistence of antigen-specific plasma cells (PCs), but key factors regulating the survival of nascent PCs remain unclear. Previously, we reported that bone marrow (BM) PCs partially organize into clusters that are enriched for long-lived PCs, suggesting that clusters are survival niches. Here, we report that acute blockade of a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) using transmembrane activator and CAML interactor (TACI)-Fc rapidly disrupts clusters and mobilizes BM PCs. CD138, a surface co-receptor that is abundant on PCs and binds APRIL but not BAFF, regulates PC retention in the BM and adhesion and motility on fibronectin. Cell-intrinsic CD138 levels control competition for survival between nascent CD138low PCs and mature CD138high PCs, and enhanced survival of CD138high PCs correlates with retention in clusters. Collectively, these results indicate that PC clusters are survival niches and that dynamic competition between new and pre-existing PCs regulates the survival of new PCs and the durability of antibody responses.

Keywords:  APRIL; CD138; CP: Immunology; bone marrow; long-lived plasma cells; plasma cells

DOI:  https://doi.org/10.1016/j.celrep.2025.116123
J Clin Invest. 2025 Aug 07. pii: e195929. [Epub ahead of print]

Overexpression of the signaling-coordinator GAB2 can play an important role in Acute Myeloid Leukemia progression.

Michael H Kramer, Stephanie N Richardson, Yang Li, Tiankai Yin, Nichole M Helton, Daniel R George, Michelle Cai, Sai Mukund Ramakrishnan, Casey Ds Katerndahl, Christopher A Miller, Timothy J Ley.

  Mutations that initiate AML can cause clonal expansion without transformation ("clonal hematopoiesis"). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific "fitness state" to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing two common AML initiating mutations (Dnmt3aR878H and Npm1cA) acquire a single copy amplification of chromosome 7, followed by activating mutations in signaling genes. We show that overexpression of a single gene on chromosome 7 (Gab2, which coordinates signaling pathways) is tolerated in the presence of the Npm1cA mutation, can accelerate the development of AML, and is important for survival of fully transformed AML cells. GAB2 is likewise overexpressed in many human AMLs with mutations in NPM1 and/or signaling genes, and also in Acute Promyelocytic Leukemia initiated by PML::RARA; the PML::RARA fusion protein may activate GAB2 by directly binding to its 5' flanking region. A similar pattern of GAB2 overexpression preceding mutations in signaling genes has been described in other human malignancies. GAB2 overexpression may represent an oncogene-driven adaptation that facilitates the action of signaling mutations, suggesting an important (and potentially targetable) "missing link" between the initiating and progression mutations associated with AML.

Keywords:  Genetics; Leukemias; Oncology

DOI:  https://doi.org/10.1172/JCI195929
Genome Biol. 2025 Aug 07. 26(1): 237

scplainer: using linear models to understand mass spectrometry-based single-cell proteomics data.

Christophe Vanderaa, Laurent Gatto.

  Analyzing mass spectrometry (MS)-based single-cell proteomics (SCP) data faces important challenges inherent to MS-based technologies and single-cell experiments. We present scplainer, a principled and standardized approach for extracting meaningful insights from SCP data using minimal data processing and linear modeling. scplainer performs variance analysis, differential abundance analysis, and component analysis while streamlining result visualization. scplainer effectively corrects for technical variability, enabling the integration of data sets from different SCP experiments. In conclusion, this work reshapes the analysis of SCP data by moving efforts from dealing with the technical aspects of data analysis to focusing on answering biologically relevant questions.

Keywords:  Batch correction; Data analysis; Data interpretation; Linear modeling; Mass spectrometry; Missing values; Proteomics; Reproducible research; Single-cell

DOI:  https://doi.org/10.1186/s13059-025-03713-4
Nat Methods. 2025 Aug 07.

Ultra-high-scale cytometry-based cellular interaction mapping.

Dominik Vonficht, Lea Jopp-Saile, Schayan Yousefian, Viktoria Flore, Inés Simó Vesperinas, Ruth Teuber, Bogdan Avanesyan, Yanjiang Luo, Caroline Röthemeier, Florian Grünschläger, Mirian Fernandez-Vaquero, Vincent Fregona, Diana Ordoñez-Rueda, Laura K Schmalbrock, Luca Deininger, Angelo Jovin Yamachui Sitcheu, Zuguang Gu, Maja C Funk, Ralf Mikut, Mathias Heikenwälder, Angelika Eggert, Arend von Stackelberg, Sebastian Kobold, Jan Krönke, Ulrich Keller, Andreas Trumpp, Ahmed N Hegazy, Cornelia Eckert, Daniel Hübschmann, Simon Haas.

Cellular interactions are of fundamental importance, orchestrating organismal development, tissue homeostasis and immunity. Recently, powerful methods that use single-cell genomic technologies to dissect physically interacting cells have been developed. However, these approaches are characterized by low cellular throughput, long processing times and high costs and are typically restricted to predefined cell types. Here we introduce Interact-omics, a cytometry-based framework to accurately map cellular landscapes and cellular interactions across all immune cell types at ultra-high resolution and scale. We demonstrate the utility of our approach to study kinetics, mode of action and personalized response prediction of immunotherapies, and organism-wide shifts in cellular composition and cellular interaction dynamics following infection in vivo. Our scalable framework can be applied a posteriori to existing cytometry datasets or incorporated into newly designed cytometry-based studies to map cellular interactions with a broad range of applications from fundamental biology to applied biomedicine.

DOI: https://doi.org/10.1038/s41592-025-02744-w
Leukemia. 2025 Aug 08.

The histone-methyltransferase DOT1L cooperates with LSD1 to control cell division in blast-phase MPN.

Karl Kapahnke, Thomas Plenge, Tabea Klaus, Manoj K Gupta, Disha Anand, Tamer T Önder, Birgit Perner, Tina M Schnöder, Felicitas R Thol, Frederik Damm, Florian H Heidel, Florian Perner.

Persistence of JAK2-mutated clones that may undergo clonal evolution and malignant transformation remains a challenge in myeloproliferative neoplasms (MPN), Novel therapeutic approaches to attenuate clonal evolution and progression to blast-phase are therefore urgently needed. LSD1 (KDM1A) inhibitors reduce symptoms and clonal burden in MPN, but whether these compounds may be effective in advanced disease stages remained so far elusive. Using a chromatin-focused CRISPR-Cas9 screen, we identified the histone methyltransferase DOT1L as a synthetic lethal target under pharmacologic LSD1 inhibition. DOT1L knockout impaired cellular fitness, reduced proliferation, and prolonged survival in xenografts. Furthermore, genetic inactivation of DOT1L increased LSD1 inhibitor sensitivity up to 100-fold resulting in cell cycle arrest and apoptosis induction in TP53 mutant blast-phase MPN. Mechanistically, we have identified a novel, non-canonical function of DOT1L which co-occupied LSD1-bound enhancers and contributed to the repression of transcriptional programs independent of its enzymatic activity. DOT1L loss cooperated with LSD1 inhibitors to activate tumor suppressive programs, while pharmacologic inhibition of DOT1Ls catalytic activity failed to elicit comparable effects. These findings indicate that leveraging DOT1L targeting via protein degradation or RNA interference, rather than conventional enzymatic inhibition, could enhance the therapeutic efficacy of LSD1 inhibitors in blast-phase MPN.

DOI: https://doi.org/10.1038/s41375-025-02719-y
bioRxiv. 2025 Aug 01. pii: 2025.08.01.668217. [Epub ahead of print]

Dynamics of Ribosomal RNA Transcription and Abundance in Normal and Leukemic Hematopoiesis.

Eleanor I Sams, Victoria K Feist, Erin M Gray, Subin S George, Charles Antony, Jill A Henrich, Julia Wald, Margaret C Dunagin, Zhengyi Wang, Noa Erlitzki, Arjun Raj, Robert A J Signer, Vikram R Paralkar.

Transcription of ribosomal RNAs (rRNAs) from rDNA repeats is the first step of ribosome biogenesis, accounting for a major portion of all cellular transcription. Often regarded as a housekeeping process, its cell-type-specific regulation in complex organ systems is largely neglected. We used rRNA FISH-Flow to profile nascent and mature rRNA levels in detail across mouse hematopoiesis, and observed that rRNA abundance is a cell-type-specific property, largely uncoupled from cell cycling or protein synthesis rates. Absolute quantification of rRNA molecules unexpectedly revealed that 28S rRNA is in excess in all cell types, most prominently in the normal myeloid lineage. In acute myeloid leukemia (AML), leukemic progenitors showed notably higher nascent and mature rRNA levels than matched normal counterparts. Across contexts of hematopoiesis, broad trends in rRNA transcription paralleled changes in accessibility but not methylation of rDNA repeats. Collectively, our work provides a detailed map of the complex dynamics of rRNAs within and between normal and leukemic hematopoiesis.

DOI: https://doi.org/10.1101/2025.08.01.668217
Cell Death Dis. 2025 Aug 02. 16(1): 586

Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells.

Tomohisa Baba, Soichiro Kumamoto, Yuta Moriguchi, Soji Morishita, Atsushi Hirao, Yoshikazu Johmura.

Accumulating evidence suggests that mitogenic signaling during cell cycle arrest can lead to severe cytotoxic outcomes, such as senescence, though the underlying mechanisms remain poorly understood. Here, we explored the link between cell cycle dynamics and the formation of PML-nuclear bodies (PML-NBs), intranuclear structures known to mediate cellular stress responses. Our findings demonstrate that PML-NBs increase their number during interphase arrest. Moreover, the activation of mitogenic ERK signaling by all-trans retinoic acid (ATRA) during CDK4/6 inhibitor-induced cell cycle arrest synergistically enhances the formation of larger PML-NBs by associating with SUMO. This enlargement, triggered by the simultaneous engagement of opposing cell cycle signals, leads to potent cytotoxicity accompanied by either terminal differentiation or apoptosis, depending on the cell type, across multiple acute myeloid leukemia (AML) cell lines. Importantly, in an AML mouse model, this combination treatment significantly improved therapeutic efficacy with minimal effects on normal hematopoiesis. Our results introduce conflicting cell cycle signal-induced cytotoxicity as a promising therapeutic strategy for AML.

DOI: https://doi.org/10.1038/s41419-025-07911-7
bioRxiv. 2025 Aug 02. pii: 2025.07.31.667978. [Epub ahead of print]

Post-Translational Modifications Remodel Proteome-Wide Ligandability.

Weichao Li, Qijia Wei, Paolo Governa, Manuel Llanos, Tzu-Yuan Chiu, Jacob M Wozniak, Appasso M Jadhav, Clara Gathmann, Jacob Cravatt, Ashok Dongre, Mia L Huang, Stefano Forli, Christopher G Parker.

Post-translational modifications (PTMs) vastly expand the diversity of human proteome, dynamically reshaping protein activity, interactions, and localization in response to environmental, pharmacologic, and disease-associated cues. While it is well established that PTMs modulate protein function, structure, and biomolecular interactions, their proteome-wide impact on small-molecule recognition-and thus druggability-remains largely unexplored. Here, we introduce a chemical proteomic strategy to delineate how PTM states remodel protein ligandability in human cells. By deploying broad profiling photoaffinity probes, we identified over 400 functionally diverse proteins whose ability to engage small molecules is impacted by phosphorylation or N-linked glycosylation status. Integration of binding site mapping with structural analyses revealed a diverse array of PTM-dependent pockets. Among these targets, we discovered that the phosphorylation status of common oncogenic KRAS mutants impact the action of small molecules, including clinically approved inhibitors. These findings illuminate an underappreciated, PTM-governed layer of proteome plasticity and uncover opportunities for the development of chemical probes to selectively target proteins in defined modification states.

DOI: https://doi.org/10.1101/2025.07.31.667978
Cell Death Dis. 2025 Aug 08. 16(1): 599

The RNA-binding protein CELF1 targets ATG5 to regulate autophagy and promote drug resistance in acute myeloid leukemia.

Xiaoyan Li, Qiyi Qian, Juejiashan Li, Lu Zhang, Lifang Wang, Dongsheng Huang, Qiuran Xu, Wenhu Chen.

Acute myeloid leukemia (AML) is a blood cancer characterized by uncontrolled growth of myeloid cells. Overcoming AML treatment resistance, particularly to anthracycline-based drugs like doxorubicin (ADR), poses a challenge. This study investigated the role of CELF1, an RNA-binding protein, in ADR resistance and autophagy regulation in AML. CELF1 expression was elevated in multiple tumor types, including AML. AML cell lines exhibit varying levels of CELF1 expression, with drug-resistant cell lines showing higher CELF1 expression compared to parental cells. CELF1 knockdown reduced drug resistance, promoted cell death, and inhibited autophagy. Mechanistic analysis identified ATG5 as a potential CELF1-regulated target gene, with CELF1 knockdown reducing ATG5 expression and mRNA decay. These findings indicate that targeting CELF1 could overcome ADR resistance in AML by modulating autophagy through ATG5 regulation, highlighting its clinical significance as a therapeutic target for enhancing ADR response in AML.

DOI: https://doi.org/10.1038/s41419-025-07926-0
Cell Signal. 2025 Aug 06. pii: S0898-6568(25)00467-X. [Epub ahead of print] 112052

TRIM10β upregulation promotes microtubule destabilization and triggers proteotoxic stress.

Heesoo Kim, Wonji Shin, Byunghoon Jeon, Sungwook Lee, Boyoun Park.

  Microtubule stability is critical for maintaining cytoskeletal integrity and is finely tuned by post-translational modifications of tubulin and its associated regulatory factors. However, it remains unclear how microtubules become destabilized under stress or disease conditions and contribute to pathogenesis. Here, we identify TRIM10β, a previously uncharacterized splice variant of TRIM10, as a microtubule-associated protein that disrupts the interaction between tubulin and End Binding protein 1 (EB1), which plays a critical role in microtubule stabilization. Moreover, TRIM10β promotes tubulin SUMOylation and cleavage of LIM domain kinase 1 (LIMK1), both of which contribute to microtubule destabilization. TRIM10β binds to calmodulin-regulated spectrin-associated protein 2 (CAMSAP2), a key regulator of non-centrosomal microtubules, and modulates its protein levels via its E3 ligase activity. Notably, TRIM10β depletion attenuates p38 phosphorylation in erythroblasts, which is essential for microtubule disassembly and polarization during enucleation, whereas its ectopic expression aberrantly enhances p38 activity, promoting microtubule disassembly in non-erythroid cells. Importantly, persistent overexpression of TRIM10β is recognized as a proteotoxic burden and rapidly degraded via the unfolded protein response (UPR) under cellular stress, thereby serving as a protective mechanism. Our findings reveal a novel role for TRIM10β in microtubule dynamics and highlight a potential regulatory mechanism in maintaining proteostasis, with its low endogenous expression possibly reflecting an evolutionary strategy to minimize proteostatic stress.

Keywords:  CAMSAP2; LIMK1; Microtubule dynamics; PTM; TRIM10; UPR

DOI:  https://doi.org/10.1016/j.cellsig.2025.112052
Cell Death Discov. 2025 Aug 05. 11(1): 366

Bridging the marrow: a co-culture-platform of leukemia cells and MS5-derived stromal cells or adipocytes.

Julia Zinngrebe, Elena Dorothea Brenner, Ferdinand Schlichtig, Ulrich Stifel, Daniel Tews, Jana Falk, Dominik Schlotter, Rahel Fitzel, Lüder-Hinrich Meyer, Klaus-Michael Debatin, Pamela Fischer-Posovszky.

In the context of acute lymphoblastic leukemia (ALL), the bone marrow microenvironment (BMM) plays a crucial role in providing pro-survival signals, as evident from the rapid spontaneous cell death observed in ex-vivo cultures of primary ALL cells. Among the diverse cell types within the BMM, bone marrow adipocytes (BMAd) exhibit significant plasticity and can constitute a substantial part of the BMM, especially during ALL therapy. However, conflicting data on the interaction between ALL cells and adipocytes have been reported, potentially arising from variations in culture systems and conditions. Our study aimed to establish a chemically defined co-culture system of leukemia cells combined with either bone marrow (BM)-derived stromal cells or adipocytes. Established B-precursor ALL cell lines, patient-derived ALL xenografts (PDX), and murine BM-derived MS5 stromal cells and adipocytes were used as model systems. Fetal calf serum and factors included in the adipogenic media significantly impacted leukemia cell viability and proliferation. Thus, we implemented a washing procedure and suitable, chemically defined media conditions into our co-culture platform. In general, ALL cell lines survived and proliferated on both stromal cells and adipocytes, whereas PDX cells exhibited a pronounced survival advantage on stromal cells compared to adipocytes. Intriguingly, the presence of adipocytes sensitized cell lines and PDX cells to chemotherapy with anthracyclines or dexamethasone when compared to co-cultures with stromal cells. Thus, utilizing the well-established MS5 cell line together with the optimized culture conditions in our co-culture system provides a reliable, open-access platform for investigating intricate interactions between bone marrow stromal cells, adipocytes, and leukemia cells.

DOI: https://doi.org/10.1038/s41420-025-02631-5
J Intern Med. 2025 Aug 08.

Precision oncology to overcome resistance in R/R AML in children and adults requires combinations of cytotoxic, targeted, and immunological treatments.

Martin Jädersten, Ingrid Lilienthal, Christer Nilsson, Louisa Fredrikson, Cornelis Jan Pronk, Kristian Løvvik Juul-Dam, Mika Kontro, Nikolas Herold.

  Although outcomes for newly diagnosed acute myeloid leukaemia (AML) have been incrementally improved over the last decades, management of relapsed and refractory (R/R) AML remains a medical challenge. A curative intent for R/R AML usually involves chemotherapy (with or without targeted therapy) with subsequent consolidation, including allogeneic haematopoietic stem cell transplantation. Despite this, long-term survival rates of R/R AML only reach approximately 10% in adults and 40% in children. Given this great unmet clinical need, this review outlines the current and emerging paradigms for preventing and treating R/R AML. Somatic mutations, gene expression, and functional drug testing are important for the selection of small molecule inhibitors of oncogenic signalling pathways (e.g., FLT3), menin inhibitors that disrupt leukemogenic programmes, inhibitors of isocitrate dehydrogenases to restore oncometabolic homoeostasis, and proapoptotic Bcl-2 homology 3 (BH3) mimetics, such as venetoclax. Targeting the recently identified resistance factor SAMHD1 promises to overcome resistance to cytarabine and fludarabine. Given the growing number of potential combinatorial drug regimens and the genetic heterogeneity of AML, real-time ex vivo drug response profiling to guide individualized treatment decisions will become an important complement. We argue that better outcomes for R/R AML critically depend on being guided by precision oncology to define the best combination of chemotherapy, targeted therapy, and immunological therapy informed by phenotypic and genotypic patient- and disease-specific parameters.

Keywords:  FLT3; IDH1; IDH2; SAMHD1; azacitidine; cladribine; cytarabine; drug screening; fludarabine; hydroxyurea; menin; resistance mechanisms; venetoclax

DOI:  https://doi.org/10.1111/joim.70004
Nat Commun. 2025 Aug 04. 16(1): 7158

Cell surface crowding is a tunable energetic barrier to cell-cell fusion.

Daniel S W Lee, Liya F Oster, Sungmin Son, Daniel A Fletcher.

Cell-cell fusion is fundamental to processes such as muscle formation and viral infection. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding reduces fusogenicity independent of how fusion is driven. We estimate that crowding presents an energetic barrier to membrane apposition on the scale of ~ 100kBT , greater than that of bare membrane fusion alone. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease their surface crowding prior to fusion. In this work, we show that cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.

DOI: https://doi.org/10.1038/s41467-025-62330-8