bims-scepro 2025-04-20 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–04–20
twenty-one papers selected by
William Grey, University of York

Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis.
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
Hematopoietic stem cell state and fate in trained immunity.
CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.
The Immune-Modulatory Function of Megakaryocytes in the Hematopoietic Niche of Myeloproliferative Neoplasms.
An erythroid-biased FOShi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia.
Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.
Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces Early Apoptotic Signaling in Multiple Myeloma.
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.
Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.
Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway.
Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.
Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.
Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
Redox signaling modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule-regulating proteins.
Proteomic-based stemness score measures oncogenic dedifferentiation and enables the identification of druggable targets.
TACC3 enhances glycolysis in bladder cancer cells through inducing acetylation of c-Myc.
Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.
Effects of PM2.5 exposure on hematopoiesis and coupled immune disorder in adult male mice.
Rethinking tubulin acetylation: From regulation to cellular adaptation.

bioRxiv. 2025 Apr 03. pii: 2025.04.01.646632. [Epub ahead of print]

Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis.

Jane J Xu, Viviana Scoca, Yi Chen, Yingqian A Zhan, Alexander Fisher, Eno-Obong Udoh, Sebastian Fernando, Besmira Alija, John Pantazi, Varun Sudunagunta, Edna Stewart, Anabella Maria D Galang, Mike Williams, Govind Bhagat, Claudia Gebhard, Valeria Visconte, Sarah Ondrejka, Ruud Delwel, Ming Hu, Richard Koche, Aaron D Viny.

Transcription factors (TFs) influencing cell fate can be dysregulated in cancer. FLI1 is crucial for hematopoietic stem/progenitor cell (HSPC) function, with STAG2 regulating FLI1 target accessibility. STAG2 depletion enhances HSPC self-renewal, but its role in leukemic transformation is unclear. We uncovered that STAG2 loss maintains FLI1 target accessibility in murine HSPCs and enhances FLI1 binding in NPM1c leukemia. In our Stag2/Npm1c/+ murine model, myeloid-biased HSPCs with increased FLI1 accessibility are reservoirs for transformation, leading to a fully penetrant leukemia. STAG2 deleted NPM1c cell lines exhibit increased chromatin accessibility and chromatin-looping of key stem and leukemia genes including FLI1-target genes CD34 and MEN1. Similarly, enrichment for a CD34+ immunophenotype was observed in co-mutant leukemia patients. STAG2 deficient cells show increased chromatin-bound MENIN and increased sensitivity to MENIN inhibition. Our findings demonstrate that altered chromatin architecture can co-opt oncogenic TF signaling, such as FLI1, as a hallmark of leukemogenesis.
Key Findings: Loss of STAG2 results in aberrant increased accessibility at FLI1 targets in mouse and human hematopoietic stem and progenitor cellsIncreased accessibility results in an increased fraction of chromatin-bound FLI1, which overlap with NPM1c targets in STAG2 NPM1c AML cellsStag2 Npm1c co-mutation leads to dysplastic murine AML phenotype arising from myeloid biased progenitors that exhibit increased Fli1 target accessibilityIn addition to higher chromatin-bound FLI1, co-mutant cells have higher chromatin-bound MENIN, including at the HOXA cluster, rendering cells highly sensitive to MENIN inhibition.
Statement of Significance: Here, we identify enhanced FLI1 chromatin accessibility as a driver of stemness and leukemic transformation in STAG2 mutant leukemia. Through comprehensive in vivo and in vitro modeling, we demonstrate that altered chromatin architecture can co-opt oncogenic TF activity, like FLI1, to drive divergent leukemia development and therapeutic response.

DOI: https://doi.org/10.1101/2025.04.01.646632
Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2
Cell Commun Signal. 2025 Apr 14. 23(1): 182

Hematopoietic stem cell state and fate in trained immunity.

Weinian Liao, Xiaodong Zai, Jun Zhang, Junjie Xu.

  Trained immunity serves as a de facto memory for innate immune responses, resulting in long-term functional reprogramming of innate immune cells. It enhances resistance to pathogens and augments immunosurveillance under physiological conditions. Given that innate immune cells typically have a short lifespan and do not divide, persistent innate immune memory may be mediated by epigenetic and metabolic changes in long-lived hematopoietic stem cells (HSCs) in the bone marrow. HSCs fine-tune their state and fate in various training conditions, thereby generating functionally adapted progeny cells that orchestrate innate immune plasticity. Notably, both beneficial and maladaptive trained immunity processes can comprehensively influence HSC state and fate, leading to divergent hematopoiesis and immune outcomes. However, the underlying mechanisms are still not fully understood. In this review, we summarize recent advances regarding HSC state and fate in the context of trained immunity. By elucidating the stem cell-intrinsic and extrinsic regulatory network, we aim to refine current models of innate immune memory and provide actionable insights for developing targeted therapies against infectious diseases and chronic inflammation. Furthermore, we propose a conceptual framework for engineering precision-trained immunity through HSC-targeted interventions.

Keywords:  Cell fate decision; Hematopoietic stem cell; Innate immune cell; Stem cell state; Trained immunity

DOI:  https://doi.org/10.1186/s12964-025-02192-1
Stem Cell Reports. 2025 Apr 05. pii: S2213-6711(25)00080-3. [Epub ahead of print] 102476

CD37 regulates the self-renewal of leukemic stem cells via integrin-mediated signaling in acute myeloid leukemia.

Jinyuan Lu, Lixin Lv, Xiaoxue Tian, Zheng Li, Yuting Ma, Nannan Li, Jian Wang, Guangming Wang, Yu Zeng, Wenjun Zhang, Jun Xu, Aibin Liang.

  Leukemic stem cells (LSCs) are a small subset of leukemia cells that drive leukemia initiation and maintenance. Herein, we report that CD37, a member of transmembrane 4 superfamily (TM4SF), regulates the survival of acute myeloid leukemia (AML) cells as well as the self-renewal of AML LSCs. The downregulation of CD37 retarded proliferation and increased apoptosis in human AML cell lines THP-1 and OCI-AML2. Deficiency of CD37 in vivo had a minimal effect on normal hematopoiesis but significantly impeded leukemia maintenance and propagation, which led to increased apoptosis and decreased cell cycle entry in AML blasts as well as impaired colony formation and declined frequency of AML LSCs in the serial transplantation. Furthermore, CD37 interacted with integrin α4β7 and activated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediated by integrin signaling. Our study provides novel insights for targeted therapy of AML, indicating CD37 as a safe and effective target for immunotherapy.

Keywords:  CD37; acute myeloid leukemia; integrin; leukemic stem cell; tetraspanin

DOI:  https://doi.org/10.1016/j.stemcr.2025.102476
bioRxiv. 2025 Apr 03. pii: 2025.04.01.646152. [Epub ahead of print]

The Immune-Modulatory Function of Megakaryocytes in the Hematopoietic Niche of Myeloproliferative Neoplasms.

Sandy Lee, Xiaoxi Yang, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and neoplastic hematopoietic stem cell (HSC) expansion. Using a murine model with MK-specific JAK2V617F expression, we establish an MPN aging model where mutant MKs drive HSC expansion and a progressive decline in wild-type HSC function. Compared to wild-type MKs, JAK2V617F MKs exhibit heightened inflammation and innate immune activation with aging, including increased antigen presentation, elevated pro-inflammatory cytokines, skewed T cell populations, and impaired T cell functions in the marrow niche. Enhanced MK immunomodulatory function is linked to mutant cell expansion and MPN progression in a chimeric murine model with co-existing wild-type and JAK2V617F mutant HSCs. LINE-1 (long-interspersed element-1), a retrotransposon linked to innate immune activation and aging, is upregulated in mutant MKs during aging in murine models. We validated that LINE-1-encoded protein ORF1p is expressed in marrow MKs in 12 of 13 MPN patients but absent in control samples from patients undergoing orthopedic surgery (n=5). These findings suggest that MKs reprogram the marrow immune microenvironment, impairing normal HSC function while promoting neoplastic expansion in MPNs. LINE-1 activation in mutant MKs may be a key driver of immune dysregulation in MPNs.
Key Points: JAK2V617F mutant MKs reprogram the marrow immune microenvironment to promote neoplastic HSC expansion in MPNs.LINE-1 activation in diseased MKs triggers chronic inflammation and immune dysfunction in MPNs.

DOI: https://doi.org/10.1101/2025.04.01.646152
Cell Stem Cell. 2025 Apr 05. pii: S1934-5909(25)00100-6. [Epub ahead of print]

An erythroid-biased FOShi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia.

Weili Liu, Xiaoru Zhang, Jinhua Liu, Lingling Pu, Lanlan Ai, Hongbao Xu, Guangrui Wang, Ding Wang, Xiaona Song, Yingnan Zhang, Ling Zhang, Jie Gao, Xiaoling Cheng, Xinxing Wang, Jingyuan Tong, Xiaowei Xie, Fang Dong, Yingchi Zhang, Ping Zhu, Zhaoli Chen, Peng Wu, Lihong Shi.

  Hypoxia imposes notable stress on organisms and even causes tissue damage; however, the cellular and molecular mechanisms underlying hypoxic adaptation and maladaptation are elusive. Here, we performed single-cell RNA sequencing to analyze hematopoietic stem and progenitor cells (HSPCs) and erythroid cells in a mouse model of high-altitude polycythemia (HAPC) mimicking long-term high-altitude hypoxia exposure. We identified a distinct erythroid-biased multipotent progenitor subset, FOShi MPP, characterized by a unique responsiveness to interferon (IFN) signaling, which expands under hypoxia conditions. This subset rapidly responds to hypoxia during re-ascent by sustaining low methylation of erythroid-priming genes, suggesting a memory function in HSPCs for faster acclimatization. Additionally, erythroid cells in HAPC mice had active metabolic and autophagic activity, as well as abundant CD47 expression that prevented the phagocytosis of erythrocytes. Finally, CD47 blockade and/or IFNα treatments alleviated erythrocytosis in HAPC mice. These approaches might constitute promising therapeutic strategies for HAPC.

Keywords:  CD47; IFNα; hematopoietic stem and progenitor cells; high-altitude polycythemia; scRNA-seq

DOI:  https://doi.org/10.1016/j.stem.2025.03.010
Stem Cell Res Ther. 2025 Apr 15. 16(1): 180

Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.

Yun Liao, Stacia Octaviani, Zhen Tian, Samuel R Wang, Chunlan Huang, Jian Huang.

  Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.

Keywords:  Hematopoietic stem cell; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial quality control; Mitochondrial transfer; Mitophagy

DOI:  https://doi.org/10.1186/s13287-025-04304-7
Nature. 2025 Apr 16.

Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs.

Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex C H Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie A Reisz, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Grace Egan, Aaron D Schimmer, Gary D Bader, John E Dick, Stephanie Z Xie, Jennifer J Trowbridge, Steven M Chan.

Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1-4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1-3,5-7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration8, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.

DOI: https://doi.org/10.1038/s41586-025-08871-w
bioRxiv. 2025 Apr 03. pii: 2025.04.02.646787. [Epub ahead of print]

Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces Early Apoptotic Signaling in Multiple Myeloma.

Erin M Kropp, Sho Matono, Olivia Y Wang, Aaron M Robida, Malathi Kandarpa, Jineigh L Grant, Bryndon J Oleson, Andrew Alt, Moshe Talpaz, Matthew Pianko, Qing Li.

Endoplasmic reticulum-associated degradation (ERAD) is essential for maintaining protein homeostasis, yet its regulatory mechanisms remain poorly understood. A major challenge in studying ERAD is the lack of specific inhibitors targeting the ERAD complex. To address this, we conducted a cell-based high-throughput screen using the FDA-repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates. Beyond its utility in identifying ERAD substrates, RTA408 exhibits strong cytotoxic effects in multiple myeloma (MM), an incurable plasma cell malignancy. RTA408 inhibits ERAD activity and rapidly induces apoptotic signaling via caspase 8 and the death-inducing signaling complex (DISC). Notably, RTA408 is cytotoxic to malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish ERAD inhibitors as valuable tools for dissecting ERAD regulation while also highlighting their potential as therapeutic agents for MM.
Highlights: We developed a cell-based screening approach to identify novel modulators of endoplasmic reticulum associated degradation (ERAD), with implications in studying ERAD biology and targeting plasma cell neoplasms.Screening of the FDA-repurposing library identified Omaveloxolone (RTA408) as an inhibitor of luminal and membrane ERAD substrate degradation, which can be leveraged to identify ERAD substrates.maveloxolone treatment rapidly induces the unfolded protein response and apoptosis that is dependent on caspase 8 and death-inducing signaling complex (DISC) in multiple myeloma cells. maveloxolone exhibits cytotoxic effects against multiple myeloma cells in vitro and in vivo and induces apoptosis in primary plasma cells from patients with relapsed/refractory myeloma.

DOI: https://doi.org/10.1101/2025.04.02.646787
Nature. 2025 Apr 16.

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.

Malgorzata Gozdecka, Monika Dudek, Sean Wen, Muxin Gu, Richard J Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L Grice, Matthew A McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L Cooper, Nisha Narayan, Sarah J Horton, Ryan Asby, Dean C Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M Quiros, Christian Frezza, James A Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A Fabre, Brian J P Huntly, George S Vassiliou.

Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

DOI: https://doi.org/10.1038/s41586-025-08980-6
Nat Commun. 2025 Apr 12. 16(1): 3492

Mutant CEBPA promotes tolerance to inflammatory stress through deficient AP-1 activation.

Maria Cadefau-Fabregat, Gerard Martínez-Cebrián, Lucía Lorenzi, Felix D Weiss, Anne-Katrine Frank, José Manuel Castelló-García, Eric Julià-Vilella, Andrés Gámez-García, Laura Yera, Carini Picardi Morais de Castro, Yi-Fang Wang, Felix Meissner, Alejandro Vaquero, Matthias Merkenschlager, Bo T Porse, Sergi Cuartero.

The CEBPA transcription factor is frequently mutated in acute myeloid leukemia (AML). Mutations in the CEBPA gene, which are typically biallelic, result in the production of a shorter isoform known as p30. Both the canonical 42-kDa isoform (p42) and the AML-associated p30 isoform bind chromatin and activate transcription, but the specific transcriptional programs controlled by each protein and how they are linked to a selective advantage in AML is not well understood. Here, we show that cells expressing the AML-associated p30 have reduced baseline inflammatory gene expression and display altered dynamics of transcriptional induction in response to LPS, consequently impacting cytokine secretion. This confers p30-expressing cells an increased resistance to the adverse effects of prolonged exposure to inflammatory signals. Mechanistically, we show that these differences primarily arise from the differential regulation of AP-1 family proteins. In addition, we find that the impaired function of the AP-1 member ATF4 in p30-expressing cells alters their response to ER stress. Collectively, these findings uncover a link between mutant CEBPA, inflammation and the stress response, potentially revealing a vulnerability in AML.

DOI: https://doi.org/10.1038/s41467-025-58712-7
Acta Biochim Biophys Sin (Shanghai). 2025 Feb 28. 57(4): 646-655

Iron overload mediates cytarabine resistance in AML by inhibiting the TP53 signaling pathway.

Yan Jia, Ling Li, Ying Li, Xunxun Zhu, Haiyan Wang, Bin Xu, Qiuping Li, Hao Zhang.

  Currently, chemotherapy remains the primary treatment for acute myeloid leukemia (AML). Drug resistance in AML cells is a critical factor contributing to the failure of chemotherapy remission and subsequent relapse. Iron overload frequently occurs in AML patients because of hematopoietic suppression or supportive blood transfusion therapy. Previous studies have indicated that iron overload may promote the progression of AML; however, the underlying mechanisms remain unclear. Our results demonstrate that, compared with TP53-wild-type AML cells, TP53-mutant AML cells exhibit increased resistance to cytarabine-induced cytotoxicity. Moreover, reducing TP53 expression in wild-type AML cells diminishes their sensitivity to cytarabine. The TP53 signaling pathway is essential for mediating cytarabine-induced apoptosis in AML cells. In this study, an iron overload model in AML cells via the use of ferric citrate is constructed. Our data indicate that iron overload can suppress the TP53/BCL2/BAX signaling pathway, counteracting cytarabine-induced apoptosis. In TP53 wild-type AML cells, TFR1 participates in iron-mediated resistance to cytarabine by regulating the entry of iron into the cells. These findings provide a foundation for further exploration of the molecular mechanisms involved in AML resistance to cytarabine.

Keywords:  TFR1; TP53; acute myeloid leukemia; iron overload

DOI:  https://doi.org/10.3724/abbs.2025027
Nature. 2025 Apr 16.

Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.

Amir Hosseini, Abhinav Dhall, Nemo Ikonen, Natalia Sikora, Sylvain Nguyen, Yuqi Shen, Maria Luisa Jurgensen Amaral, Alan Jiao, Felice Wallner, Philipp Sergeev, Yuhua Lim, Yuanqin Yang, Binje Vick, Kimihito Cojin Kawabata, Ari Melnick, Paresh Vyas, Bing Ren, Irmela Jeremias, Bethan Psaila, Caroline A Heckman, M Andrés Blanco, Yang Shi.

Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.

DOI: https://doi.org/10.1038/s41586-025-08915-1
bioRxiv. 2025 Apr 01. pii: 2025.03.31.646474. [Epub ahead of print]

Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.

Leeba Ann Chacko, Hidenori Nakaoka, Richard Morris, Wallace Marshall, Vaishnavi Ananthanarayanan.

Mitochondria are not produced de novo in newly divided daughter cells, but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast 'mother machine', we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the 'sizer' mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division: cells born with lower than average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modelling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Taken together, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.

DOI: https://doi.org/10.1101/2025.03.31.646474
Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027

Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.

Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.

  Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures

DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
Redox Biol. 2025 Apr 03. pii: S2213-2317(25)00139-9. [Epub ahead of print]83 103626

Redox signaling modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule-regulating proteins.

Christian Conze, Nataliya I Trushina, Nanci Monteiro-Abreu, Lisha Singh, Daniel Villar Romero, Eike Wienbeuker, Anna-Sophie Schwarze, Michael Holtmannspötter, Lidia Bakota, Roland Brandt.

  Many life processes are regulated by physiological redox signaling, but excessive oxidative stress can damage biomolecules and contribute to disease. Neuronal microtubules are critically involved in axon homeostasis, regulation of axonal transport, and neurodegenerative processes. However, whether and how physiological redox signaling affects axonal microtubules is largely unknown. Using live cell imaging and super-resolution microscopy, we show that subtoxic concentrations of the central redox metabolite hydrogen peroxide increase axonal microtubule dynamics, alter the structure of the axonal microtubule array, and affect the efficiency of axonal transport. We report that the mitochondria-targeting antioxidant SkQ1 and the microtubule stabilizer EpoD abolish the increase in microtubule dynamics. We found that hydrogen peroxide specifically modulates the phosphorylation state of microtubule-regulating proteins, which differs from arsenite as an alternative stress inducer, and induces a largely non-overlapping phosphorylation pattern of MAP1B as a main target. Cell-wide phosphoproteome analysis revealed signaling pathways that are inversely activated by hydrogen peroxide and arsenite. In particular, hydrogen peroxide treatment was associated with kinases that suppress apoptosis and regulate brain metabolism (PRKDC, CK2, PDKs), suggesting that these pathways play a central role in physiological redox signaling and modulation of axonal microtubule organization. The results suggest that the redox metabolite and second messenger hydrogen peroxide induces rapid and local reorganization of the microtubule array in response to mitochondrial activity or as a messenger from neighboring cells by activating specific signaling cascades.

Keywords:  Axon; Hydrogen peroxide; Microtubules; Redox signalling; Tau

DOI:  https://doi.org/10.1016/j.redox.2025.103626
Cell Genom. 2025 Apr 15. pii: S2666-979X(25)00107-7. [Epub ahead of print] 100851

Proteomic-based stemness score measures oncogenic dedifferentiation and enables the identification of druggable targets.

Clinical Proteomic Tumor Analysis Consortium

  Cancer progression and therapeutic resistance are closely linked to a stemness phenotype. Here, we introduce a protein-expression-based stemness index (PROTsi) to evaluate oncogenic dedifferentiation in relation to histopathology, molecular features, and clinical outcomes. Utilizing datasets from the Clinical Proteomic Tumor Analysis Consortium across 11 tumor types, we validate PROTsi's effectiveness in accurately quantifying stem-like features. Through integration of PROTsi with multi-omics, including protein post-translational modifications, we identify molecular features associated with stemness and proteins that act as active nodes within transcriptional networks, driving tumor aggressiveness. Proteins highly correlated with stemness were identified as potential drug targets, both shared and tumor specific. These stemness-associated proteins demonstrate predictive value for clinical outcomes, as confirmed by immunohistochemistry in multiple samples. The findings emphasize PROTsi's efficacy as a valuable tool for selecting predictive protein targets, a crucial step in customizing anti-cancer therapy and advancing the clinical development of cures for cancer patients.

Keywords:  biomarkers; cancer; drug targets; kinase activity; machine learning; mass spectrometry; multiomics; proteomics; stemness; tumor plasticity

DOI:  https://doi.org/10.1016/j.xgen.2025.100851
Cell Death Dis. 2025 Apr 17. 16(1): 311

TACC3 enhances glycolysis in bladder cancer cells through inducing acetylation of c-Myc.

Zhirui Lin, Falian Liang, Gengde Hong, Xizhen Jiang, Qingling Zhang, Mengyao Wang.

The proliferation of bladder cancer (BC) cells is driven by metabolic reprogramming, marked by a glycolytic dependency to sustain uncontrolled growth. While Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) is known to promote BC progression and correlate with poor prognosis, the mechanisms underlying its upregulation and role in aerobic glycolysis remain unclear. Here, we identify E2F3 as a direct transcriptional activator of TACC3, with its amplification in BC driving elevated TACC3 expression. TACC3 overexpression enhances glycolysis, increasing glucose consumption, lactate production, and expression of glycolytic enzymes (e.g., GLUT1, HK2, PFKFB3), while its knockdown suppresses these effects. Pharmacological inhibition of glycolysis abrogates TACC3-driven tumor growth in vitro and in vivo. Mechanistically, TACC3 interacts with c-Myc, promoting its acetylation at lysine 323 (K323) by recruiting the acetyltransferase PCAF and antagonizing the deacetylase SIRT1. This acetylation stabilizes c-Myc, amplifying its transcriptional activation of glycolytic targets. Our findings establish TACC3 as a critical regulator of c-Myc-driven metabolic reprogramming in BC, highlighting its potential as a therapeutic target to disrupt glycolysis and oncogenic c-Myc signaling.

DOI: https://doi.org/10.1038/s41419-025-07645-6
J Leukoc Biol. 2025 Apr 15. pii: qiaf043. [Epub ahead of print]

Hematopoietic stem and progenitor cells fine-tunning the "sweet" of trained immunity.

Jiawei Li, Hui Wang, Sheng Xia.

  Recent studies have challenged the traditional view of innate immunity as non-specific and transient by demonstrating that innate immune cells can develop immune memory in response to various activating factors, a phenomenon known as trained immunity. This process involves epigenetic modifications, such as changes in chromatin accessibility, and metabolic reprogramming, which can provide protection against unrelated pathogens but may also trigger immune-mediated damage. This review summarizes the current understanding of innate immune memory, with a particular focus on recent findings regarding the training of innate immune cells at the hematopoietic stem and progenitor cell stage. We present observations of trained immunity in innate immune cells, summarize key activating factors and underlying mechanisms, and propose potential host-directed immunotherapeutic strategies and preventive measures based on trained immunity. Our aim is to highlight the biological significance of trained immunity and its potential applications in enhancing long-term immunity, improving vaccine efficacy, and preventing immune-related diseases.

Keywords:  epigenetic changes; hematopoietic stem and progenitor cells; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1093/jleuko/qiaf043
J Environ Sci (China). 2025 Sep;pii: S1001-0742(24)00442-X. [Epub ahead of print]155 442-453

Effects of PM2.5 exposure on hematopoiesis and coupled immune disorder in adult male mice.

Li Ma, Yang Wang, Hao Wang, Lingyu Ren, Yuqiong Guo, Liyao Qin, Zhihua Gong, Guangke Li, Nan Sang.

  Fine particulate matter, namely PM2.5, increases the risk of morbidity and mortality in various systems, including the hematopoietic and immune systems. However, there is limited experimental evidence supporting the association between PM2.5 exposure and hematopoietic outcomes as most studies focus on epidemiological data. In this study, adult male mice were exposed to PM2.5 for a long time to investigate hematopoietic toxicity. There were significant increases in red blood cells (RBC), hemoglobin (HGB), and white blood cells (WBC) in peripheral blood after 5-month real-environmental PM2.5 exposure, indicating elevated circulatory inflammation and potential hematopoietic abnormality. Moreover, we observed abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs), along with altered mRNA levels of hematopoietic genes and increased proinflammatory factors in the bone marrow (BM). Transcriptomic analysis of BM cells suggested that PM2.5 exposure activated immune responses associated with lymphocytes. Then, PM2.5 exposure via intratracheal instillation was performed for 8 weeks to verify the toxic effect. The results of the complete blood count were similar to those of real-environmental exposure, with drastic changes in the number and function of HSPCs, as well as mRNA levels of the hematopoietic genes and increased inflammatory factors in the BM being detected. Furthermore, lymphocyte subsets changed significantly in the BM and spleen, confirming immune disorder following PM2.5 exposure. In conclusion, PM2.5 interfered with the process of BM hematopoiesis by triggering inflammation and leading to immune disorder. Our study provided experimental evidence for the hematopoietic toxicity of PM2.5 and highlighted the significance of reducing air pollution.

Keywords:  Bone marrow hematopoiesis; Immune disorder; PM(2.5) exposure

DOI:  https://doi.org/10.1016/j.jes.2024.08.030
Curr Opin Cell Biol. 2025 Apr 11. pii: S0955-0674(25)00050-X. [Epub ahead of print]94 102512

Rethinking tubulin acetylation: From regulation to cellular adaptation.

Lisa Donker, Susana A Godinho.

Ever since its discovery, acetylation of α-tubulin on lysine 40 (K40) has been associated with the presence of long-lived, stable microtubules. Indeed, later studies revealed that acetylation protects microtubules from mechanical breakage, yet the functional consequences of this modification at the cellular level are only beginning to emerge. Here, we outline novel insights into the mechanisms controlling tubulin acetylation, and its impact on microtubule properties and cellular functions. Finally, we highlight recent advances suggesting that tubulin acetylation can also occur as a dynamic modification in response to a variety of cellular stresses. These observations shed new light on the cell biological functions of tubulin acetylation and give rise to the notion that this modification could be a universal mechanism that allows cells to adapt to changes in their environment or intracellular state.

DOI: https://doi.org/10.1016/j.ceb.2025.102512