bims-scepro 2025-09-07 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–09–07
23 papers selected by
William Grey, University of York

A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging.
The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.
Resolving leukemic stem cell heterogeneity and plasticity with single-cell multiomics.
Molecular signature and regulatory network of human umbilical cord mesenchymal stromal cells as a niche for hematopoietic stem cells and progenitors.
Hematopoietic stem and progenitor cells as a reservoir for trained immunity.
TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
Stage-specific regulation by autophagy-related transcription factors drives hematopoietic stem cell formation.
Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.
Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function.
Identification of a CD138-negative therapy-resistant subpopulation in multiple myeloma with vulnerability to splicing factor inhibition.
Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.
SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.
METTL13 Promotes Pre-Leukemic Transformation and the Development of Pediatric Leukemia.
UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.
Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice.
Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case.
Transcript isoform diversity defines molecular subtypes and prognosis in acute myeloid leukemia through long-read sequencing.
Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.
Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.
Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis.
The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.

Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01007-1. [Epub ahead of print]44(9): 116236

A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.

Asiri Ediriwickrema, Yusuke Nakauchi, Amy C Fan, Thomas Köhnke, Xiaoyi Hu, Bogdan A Luca, YeEun Kim, Sreejith Ramakrishnan, Margaret Nakamoto, Daiki Karigane, Miles H Linde, Armon Azizi, Aaron M Newman, Andrew J Gentles, Ravindra Majeti.

  Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to meet the evolving demands of an organism. Adult human MPPs remain ill defined, whereas mouse MPPs are well characterized, with distinct immunophenotypes and lineage potencies. Using multi-omic single-cell analyses and functional assays, we identified distinct human MPPs within Lin-CD34+CD38dim/lo adult bone marrow with unique biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We identified a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69- erythroid-biased MPP. We used this updated hematopoietic stem and progenitor cell (HSPC) profile to study human and mouse bone marrow cells and observe unique cell-type-specific homology between species and cell-type-specific changes associated with human aging. By identifying and functionally characterizing adult MPP sub-populations, we provide a framework for future studies in hematopoiesis.

Keywords:  CP: Stem cell research; aging; bone marrow; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; hematopoietic stem cells; multipotent progenitors; oligopotent progenitors; single-cell RNA sequencing and single-cell multi-omics

DOI:  https://doi.org/10.1016/j.celrep.2025.116236
Cell Rep. 2025 Aug 26. pii: S2211-1247(25)00964-7. [Epub ahead of print]44(9): 116193

Distinct roles for NF-κB in hematopoietic stem cells and the bone marrow milieu in promoting hematopoietic aging.

Jennifer J Chia, Apeksha Singh, Yu-Sheng Lin, Noa Popko, David Mastro, Yi Liu, Tiffany Tran, Jennifer K King, Dinesh S Rao, Alexander Hoffmann.

  Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes aging phenotypes. Nuclear factor κB (NF-κB) both responds to and directs inflammation, and we present an experimental model of elevated NF-κB activity ("inhibitor of κB deficient" [IκB-]) to dissect its role in hematopoietic aging phenotypes. We find that while elevated NF-κB activity is not sufficient for HSC accumulation, HSC-autonomous NF-κB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB- proinflammatory bone marrow milieu, as observed functionally, epigenomically, and transcriptomically. A single-cell RNA sequencing (scRNA-seq) HSPC labeling framework enables comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NF-κB activity and quiescence but not myeloid bias. These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.

Keywords:  C/EBP; CP: Immunology; CP: Stem cell research; NF-κB; bone marrow cytokine milieu; bone marrow niche; hematopoietic aging; hematopoietic stem cell impairment; inflammaging; microenvironment; myeloid bias; stem cell aging

DOI:  https://doi.org/10.1016/j.celrep.2025.116193
Stem Cells. 2025 Sep 04. pii: sxaf059. [Epub ahead of print]

The impact of donor and recipient age on post-transplantation clonality in murine haematopoiesis.

Lars Thielecke, Kalpana Nattamai, Aishlin Hassan, Ingmar Glauche, Hartmut Geiger, Kerstin Cornils.

  The sustained production of blood and immune cells is driven by a pool of hematopoietic stem cells (HSCs) and their offspring. Due to the intrinsic heterogeneity of HSCs, the composition of emergent clones changes over time, leading to a reduced clonality in aging mice and humans. Theoretical analyses suggest that clonal conversion rates and clonal complexity depend not only on HSC heterogeneity, but also on additional stress conditions. These insights are particularly relevant in the context of stem cell transplantations, which still remain the only curative option for many hematologic diseases, increasingly considered viable for elderly individuals. However, age-related clonal changes post-transplantation are not well understood. To address this, we conducted a barcode-based assessment of clonality to investigate post-transplantation changes in both homo- and hetero-chronic settings, combined with low- and high-intensity pre-conditioned recipients. A robust and polyclonal engraftment was observed across all groups, but with distinct differences in barcode diversity. In particular, transplanted aged HSCs showed no changes in clonality, regardless of recipient age or pre-conditioning. Young HSCs transplanted into severely pre-conditioned old hosts as well as under reduced pre-conditioning, allowed for full lymphoid reconstitution, but showed substantial differences in clonality. Also, myeloid lineage bias, a hallmark of aged HSCs, was confirmed at a clonal level across all experimental groups. Overall, we found that aged HSCs generally maintain clonal diversity similar to young HSCs, but notable differences emerge under hetero-chronic conditions and varying pre-conditioning regimens. These findings challenge current paradigms and underscore the complex interactions between aging and transplantation conditions.

Keywords:  aging; cellular barcodes; clonality; hematopoiesis; stem cell transplantation

DOI:  https://doi.org/10.1093/stmcls/sxaf059
Semin Hematol. 2025 Aug 05. pii: S0037-1963(25)00033-2. [Epub ahead of print]

Resolving leukemic stem cell heterogeneity and plasticity with single-cell multiomics.

Frank Y Huang, Andreas Trumpp, Patrick Stelmach.

  Acute myeloid leukemia (AML) is an aggressive blood cancer in which disease initiation and relapse are driven by leukemic cells with stem-like properties, known as leukemic stem cells (LSCs). The LSC compartment is highly heterogenous and this contributes to differences in therapy response. This heterogeneity is determined by genetic and nongenetic factors including somatic mutations, the cell of origin, transcriptional and epigenetic states as well as phenotypic plasticity. While this complicates the identification and eradication of LSCs, it also presents an opportunity to tailor therapeutic strategies to the phenotypic and functional states of LSCs present in a patient, exploiting their specific vulnerabilities. The emergence of single-cell multiomics technologies has transformed our ability to dissect cellular heterogeneity in AML, enabling simultaneous interrogation of genomic, transcriptomic, epigenomic and proteomic layers and providing high-resolution molecular snapshots of individual cells. In this review, we discuss causes and consequences of LSC heterogeneity, highlight advances in single-cell multiomics technologies to resolve it and outline how they can address shortcomings in our understanding of LSC heterogeneity and plasticity to revolutionize diagnostics and disease monitoring of AML.

Keywords:  Acute myeloid leukemia (AML); Leukemic stem cells (LSCs); Plasticity; Therapy response and resistance; Venetoclax

DOI:  https://doi.org/10.1053/j.seminhematol.2025.07.001
Stem Cells. 2025 Sep 02. pii: sxaf057. [Epub ahead of print]

Molecular signature and regulatory network of human umbilical cord mesenchymal stromal cells as a niche for hematopoietic stem cells and progenitors.

Pornprapa Srimorkun, Kittisak Suanpan, Korakot Atjanasuppat, Piamsiri Sawaisorn, Werapath Somchit, Teerapong Siriboonpiputtana, Oytip Nathalang, Suradej Hongeng, Sawang Petvises, Usanarat Anurathapan.

  The fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network supporting self-renewal and quiescence within a niche. Umbilical cord mesenchymal stromal cells (UC-MSCs) are classified as an alternative niche for the expansion of hematopoietic stem and progenitor cells (HSPCs). The molecular mechanisms by which UC-MSCs regulate hematopoiesis are still not fully understood. In this study, the cocultures of UC-MSCs and umbilical cord blood CD34+ (UCB-CD34+) cells were established. Immunophenotype, cell proliferation, and hematopoietic function of UCB-CD34+ cells were evaluated on days 0 to 7. UC-MSCs promoted UCB-CD34+ cell proliferation but were less effective at preserving their stemness. Notably, UC-MSCs promoted the myeloid lineage commitment, significantly observed on day 3. Integrative transcriptomic analysis highlighted the molecular signature and regulatory networks of UC-MSCs. The long non-coding RNA (lncRNA)-RNA binding protein (RBP) interaction network and lncRNA cis- and trans-regulatory networks were evident. The significant 3-gene modules and a set of 10-hub genes were identified in the protein-protein interaction (PPI) network, including RPS16, CD74, RPL35, COX7C, RPL38, RPS28, RPS27, RPS10, TARDBP, and TOMM7. These findings exemplify the niche activity of UC-MSCs in regulating cell differentiation, genomic stability maintenance, and modulation of the hematopoietic supportive niche. The transcriptional landscape, together with the identified regulatory networks, gene modules, and key hub genes provide new insights into the molecular mechanisms of UC-MSCs and establish a basis for refining ex vivo culture systems for therapeutic HSC expansion.

Keywords:  CD34+; Hematopoiesis; Hematopoietic stem cells (HSCs); Mesenchymal stem cells (MSCs); Transcriptional regulation; Umbilical cord

DOI:  https://doi.org/10.1093/stmcls/sxaf057
Elife. 2025 Sep 04. pii: e106610. [Epub ahead of print]14

Hematopoietic stem and progenitor cells as a reservoir for trained immunity.

Brandon T Tran, Vidthiya Jeyanathan, Ruoqiong Cao, Eva Kaufmann, Katherine Y King.

  Human and murine studies reveal that innate immune cells are able to mount enhanced responses to pathogens after primary inflammatory exposure. Innate immune memory has been shown to last for months to years, longer than the lifespan of most innate immune cells. Indeed, long-lived hematopoietic stem and progenitor cells (HSPCs) serve as a cellular reservoir for innate immune memory. In this review, we summarize the evidence that innate immune memory is epigenetically encoded in HSPCs, and we consider whether HSPC subpopulations with differentiation bias, cell autonomous epigenetic reprogramming, or both features underlie the phenomenon of central trained immunity. We further profile the significant implications of central trained immunity in stem cell transplant, aging, inflammatory diseases, and vaccination strategies for the future.

Keywords:  epigenetics; hematopoietic progenitor cells; hematopoietic stem cells; immunology; inflammation; innate immune memory; metabolism; trained immunity

DOI:  https://doi.org/10.7554/eLife.106610
bioRxiv. 2025 Aug 31. pii: 2025.08.28.672283. [Epub ahead of print]

TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.

Ahmed M Mamdouh, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Nishtha Chitkara, Leah Hogdal, R Coleman Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy, decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this (post-MOMP brake) is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.

DOI: https://doi.org/10.1101/2025.08.28.672283
Autophagy. 2025 Aug 28. 1-3

Stage-specific regulation by autophagy-related transcription factors drives hematopoietic stem cell formation.

Jia Chen, Jiayi Zheng, Xiaoya Chen, Gangjue Tang, Yan Huang.

  Macroautophagy/autophagy critically regulates hematopoietic stem cell (HSC) development and differentiation, yet the upstream transcriptional mechanisms governing autophagy during dynamic developmental processes remain poorly characterized. Here, we combined single-cell RNA sequencing (scRNA-seq) with metaTF to dissect six consecutive stages of murine HSC development, spanning the aorta-gonad-mesonephros (AGM) region at embryonic day (E) 10.5, the fetal liver at E12.5/E14.5, and adult bone marrow. Beyond transcript abundance alone, we found that the activity of autophagy-related transcription factors (TFs) more robustly characterized cell-type specificity, particularly distinguishing T1 and T2 pre-HSCs, and identified 32 cell-type-specific autophagy-related TFs. Stage-specific autophagy-related TF-target gene networks constructed for T1 and T2 revealed functional partitioning of the pre-HSC stage: an early T1 phase characterized by elevated autophagy activity, and a later T2 phase primarily involved in proliferation and maturation. These findings highlight the temporal regulation exerted by autophagy-related TFs during embryonic hematopoiesis and underscore the importance of autophagy in stem cell fate decision.Abbreviations: HSC: hematopoietic stem cell; TF: transcription factor.

Keywords:  Autophagy; TF activity; metaTF; mouse embryos; single cells

DOI:  https://doi.org/10.1080/15548627.2025.2551671
EMBO Mol Med. 2025 Aug 29.

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.

Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, Sébastien Letard, Nadine Carbuccia, Armelle Goubard, Rémy Castellano, Yves Collette, Julien Vernerey, Isabelle Vigon, Jean-Max Pasquet, Patrice Dubreuil, Sophie Lopez, Paulo De Sepulveda.

  The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

Keywords:  Iadademstat; Inhibitor; Kinase; Leukemia; Palbociclib

DOI:  https://doi.org/10.1038/s44321-025-00296-2
Sci Adv. 2025 Aug 29. 11(35): eadr5867

Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function.

Shweta Singh, Kristbjorn O Gudmundsson, Tanmoy Sarkar, Brad L Jakubison, Holly M Morris, Sandra Burkett, Karim Baktiar, Gary T Pauly, Dina M Sigano, Joel P Schneider, Lino Tessarollo, Jonathan R Keller.

Hematopoietic malignancies emerge through the acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Some mutations impart a selective growth advantage to HSPCs, which expand and contribute to mature blood cells. This expansion is termed clonal hematopoiesis (CH). Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of hematopoietic cells. HSPCs express low levels of Id1 that is induced by growth factors and other mediators of inflammatory during stress to promote HSPC expansion. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing Id1 expression may reduce CH. Genetic ablation of Id1 in Tet2-/- HSPCs reduces HSPC expansion/CH, extramedullary hematopoiesis, myeloid skewing, and genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence, and apoptosis were increased, and proliferation decreased in Tet2-/-;Id1-/- HSPCs. Thus, ID1 may represent a therapeutic target to reduce CH and delay the onset of disease.

DOI: https://doi.org/10.1126/sciadv.adr5867
Blood Cancer Discov. 2025 Sep 02.

Identification of a CD138-negative therapy-resistant subpopulation in multiple myeloma with vulnerability to splicing factor inhibition.

Takahiro Kamiya, Masahiko Ajiro, Motohiko Oshima, Shuhei Koide, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Akiho Tsuchiya, Satoshi Kaito, Naoki Itokawa, Ryoji Ito, Kiyoshi Yamaguchi, Yoichi Furukawa, Bahityar Rahmutulla, Atsushi Kaneda, Takayuki Shimizu, Noriko Doki, Taku Kikuchi, Nobuhiro Tsukada, Masayuki Yamashita, Shinichiro Okamoto, Akihide Yoshimi, Keisuke Kataoka, Atsushi Iwama.

The molecular basis of therapy resistance in multiple myeloma (MM) remains poorly understood. Here, we performed single-cell RNA sequencing coupled with VDJ-targeted sequencing of highly purified primary MM cells from patient bone marrow. This approach uncovered cellular heterogeneity and phenotypic plasticity along the CD138 axis, accompanied by drastic epigenetic alterations. Notably, therapy-resistant subpopulations were identified within a minor fraction of CD138- MM cells, and were shown via CRISPR/Cas9 screening to be vulnerable to splicing pathway inhibition. Consistently, this fraction of CD138- MM cells showed increased differential splicing associated with overexpression of SR protein family splicing factors. Among these splicing factors, RNA-binding protein 39 (RBM39) was specifically overexpressed in therapy-resistant cells and involved in aberrant splicing. Both genetic and pharmacological RBM39 inhibition exhibited a significant selective lethal effect on therapy-resistant CD138- MM cells. Collectively, our findings identify distinct therapy-resistant MM subpopulations and highlight the splicing pathway as a promising therapeutic target.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0340
Cell Stem Cell. 2025 Sep 04. pii: S1934-5909(25)00270-X. [Epub ahead of print]32(9): 1403-1420.e8

Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.

Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Anna A Khachatrian, Elsa Molina, Michael P Snyder, Sheldon R Morris, Twyman Clements, Alysson R Muotri, Thomas Whisenant, Ludmil B Alexandrov, Catriona H M Jamieson.

  Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.

Keywords:  ADAR1; APOBEC3; aging; cell cycle; clonal hematopoiesis; dark genome; hematopoietic stem and progenitor cells; low-earth orbit; nanobioreactor; repetitive elements

DOI:  https://doi.org/10.1016/j.stem.2025.07.013
Haematologica. 2025 Sep 04.

SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.

Miao Chen, Wenze Li, Yuan Tao, Chenglong Hu, Rui Ge, Sijing Kang, Pengjie Yue, Cheuk Him Man, Lan Wang, Xiaojing Yan.

Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and shows to play an important role in lipid metabolism regulation. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role of in maintaining AML cell survival and regulating its drug sensitivity, and further developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.

DOI: https://doi.org/10.3324/haematol.2024.287269
Nat Genet. 2025 Aug 28.

Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis.

Matthew A McLoughlin, Sruthi Cheloor Kovilakam, William G Dunn, Muxin Gu, Jake Tobin, Yash Pershad, Nicholas Williams, Daniel Leongamornlert, Kevin Dawson, Laura Bond, Ludovica Marando, Sean Wen, Rachael Wilson, Giampiero Valenzano, Vasiliki Symeonidou, Justyna Rak, Aristi Damaskou, Malgorzata Gozdecka, Xiaoxuan Liu, Clea Barcena, Josep Nomdedeu, Paul Costeas, Ioannis D Dimitriou, Edoardo Fiorillo, Valeria Orrù, Jose Guilherme de Almeida, Thomas McKerrell, Matthew Cullen, Irina Mohorianu, Theodora Foukaneli, Alan J Warren, Chi Wong, George Follows, Anna L Godfrey, Emma Gudgin, Francesco Cucca, Eoin McKinney, E Joanna Baxter, Moritz Gerstung, Jonathan Mitchell, Daniel Wiseman, Alexander G Bick, Margarete Fabre, Pedro M Quiros, Jyoti Nangalia, Siddhartha Kar, George S Vassiliou.

The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.

DOI: https://doi.org/10.1038/s41588-025-02296-x
bioRxiv. 2025 Aug 30. pii: 2025.08.29.673071. [Epub ahead of print]

METTL13 Promotes Pre-Leukemic Transformation and the Development of Pediatric Leukemia.

Sabina Enlund, Chae-Eun Lim, Isabella Hoang, Sonali Joshi, Amanda Ramilo Amor, Cecilia Thomsson, Indranil Sinha, Shahrzad Shirazi Fard, Anna Nilsson, Ola Hermanson, Qingfei Jiang, Frida Holm.

Post-transcriptional RNA modifications, such as N6-methyladenosine (m6A) methylation and adenosine to inosine (A-to-I) editing, are critical regulators of hematopoietic stem cell (HSC) self-renewal and differentiation, yet their precise contributions to malignant transformation are not fully elucidated. In this study, we uncovered the epitranscriptomic landscape caused by knockdown of genes from the methyltransferase (METTL)-family in hematopoietic stem and progenitor cells (HSPCs). We identified both converging and distinct roles of METTL3 and METTL14, known members of the m6A writer complex, as well as orphan gene METTL13. Notably, METTL13 was uniquely upregulated by adenosine deaminase acting on RNA 1 (ADAR1) overexpression, while other METTL genes were downregulated. Knockdown of METTL13 altered the expression of multiple genes involved in oncogenic development in HSPCs. Furthermore, METTL13 was associated with a high-risk profile in pediatric T-cell acute lymphoblastic leukemia (T-ALL), and functional studies confirmed that METTL13 is required for T-ALL cell proliferation and survival both in vitro and in vivo. Collectively, our results indicate a previously unrecognized, oncogenic role for METTL13 in pre-leukemic transformation and T-ALL pathogenesis.

DOI: https://doi.org/10.1101/2025.08.29.673071
J Clin Invest. 2025 Sep 04. pii: e193011. [Epub ahead of print]

UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.

Ge Dong, Jingjing Liu, Wenyan Jin, Hongxi Zhou, Yuchen Wen, Zhiqin Wang, Keyao Xia, Jianlin Zhang, Linxiang Ma, Yunxi Ma, Lorie Chen Cai, Qiufan Zhou, Huaquan Wang, Wei Wei, Ying Fu, Zhigang Cai.

  VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that murine mutants with about 70% loss of Uba1 in neutrophils induced non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss while depletion of Uba1 in B or T cells, or in megakaryocytes induced corresponsive cell death but these mutants appeared normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants were viable. Among the tested models, only depletion of Uba1 in neutrophils induced autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, occurrence of vacuoles in myeloid cells, splenomegaly and dermatitis. Residual Uba1 was about 30% in the mutant neutrophils, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will assist understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.

Keywords:  Hematology; Hematopoietic stem cells; Inflammation; Neutrophils; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/JCI193011
bioRxiv. 2025 Aug 30. pii: 2025.08.26.672314. [Epub ahead of print]

Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice.

Melissa Rowe, Joanna Tober, Vivian Ortiz, Riham Smoom, Yehuda Tzfati, Nancy A Speck, Klaus H Kaestner.

Extremely short telomeres cause bone marrow failure in telomere biology disorder (TBDs) patients. Here, we employed the recently developed 'Telomouse' with human-length telomeres resulting from a single amino acid substitution in the helicase Rtel1 (Rtel1M492K/M492K) to determine the effects of the short telomeres on the bone marrow and hematopoiesis. Under homeostatic conditions, Telomice have notably short telomeres but normal hematopoiesis. However, when forced to repopulate following repeated treatment with 5-fluoro-uracil or upon bone marrow transplantation into lethally irradiated mice, bone marrow progenitor cells are significantly depleted in Telomice compared to wild-type controls. This effect is associated with increased frequency of telomere repeat arrays too short to be detected by fluorescence in situ hybridization in the bone marrow of Telomice.

DOI: https://doi.org/10.1101/2025.08.26.672314
Hum Gene Ther. 2025 Sep 01.

Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case.

Pilar Puig-Serra, Ana Hinckley-Boned, María Tristán-Manzano, Paula Rio, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Francisco Martín.

  Seven cases of hematological malignancy reported in recipients of Skysona™ (elivaldogene autotemcel) have reignited long-standing concerns about insertional mutagenesis in lentiviral vector (LV)-based gene therapy. Here, we dissect the molecular and clinical evidence underlying these events, place them in the broader context of over 300 patients treated with LV-modified hematopoietic stem and progenitor cells (HSPCs), and review the real-world safety record of LV-engineered chimeric antigen receptor T cells. We show that cancers associated with Skysona are mechanistically linked to the use of a potent viral MNDU3 promoter probably combined with intensive conditioning and growth-factor support, whereas LV products employing weak or physiological promoters continue to display an excellent safety profile. With event rates <0.6/100 patient-years, lower than those after autologous HSCT, the therapeutic index of approved LV-HSPC advanced therapy medicinal products remains favorable. Ongoing optimization of vector design, conditioning, and long-term surveillance, together with emerging genome-editing platforms, is expected to further mitigate residual risk.

Keywords:  Skysona; gene therapy safety; genotoxicity; hematopoietic stem cells; insertional mutagenesis; lentiviral vectors

DOI:  https://doi.org/10.1177/10430342251372474
Cell Rep. 2025 Sep 02. pii: S2211-1247(25)00987-8. [Epub ahead of print]44(9): 116216

Transcript isoform diversity defines molecular subtypes and prognosis in acute myeloid leukemia through long-read sequencing.

Xiaoguang Shi, Shuai Wang, Shuting Yu, Fangying Jiang, Jinzeng Wang, Yao Dai, Jincan Li, Ruihong Zhang, Tong Yin, Yuting Dai, Hai Fang, Junmin Li, Hongming Zhu, Shengyue Wang.

  Acute myeloid leukemia (AML) is a genetically complex and clinically heterogeneous hematopoietic malignancy. This study employs long-read transcriptome analysis using oxford nanopore technologies sequencing on 60 primary AML bone marrow samples. This approach delivers comprehensive isoform-level resolution of splicing abnormalities and overcomes limitations of short-read sequencing. We detect extensive AML-specific splicing anomalies and identify 119,278 previously unannotated transcript isoforms. Of these, 80,294 (67.31%) contain complete open reading frames, with 9,812 (12.22%) validated using liquid chromatography-tandem mass spectrometry. Quantitative analysis in 175 RNA sequencing samples enables non-negative matrix factorization clustering, defining distinct molecular subtypes. These isoform-defined subtypes exhibit strong correlations with patient prognosis, indicating their potential as biomarkers for clinical classification. The findings highlight alternative splicing as a major contributor to AML molecular heterogeneity and provide a valuable foundation for advancing precision medicine and developing innovative therapeutic strategies targeting splicing abnormalities in AML.

Keywords:  CP: Cancer; CP: Genomics; acute myeloid leukemia; alternative splicing; long-read RNA sequencing; molecular subtypes; non-negative matrix factorization; transcript isoform

DOI:  https://doi.org/10.1016/j.celrep.2025.116216
Nat Commun. 2025 Sep 02. 16(1): 8181

Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.

Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan.

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that either restoring ALDH16A1 levels or inhibiting TXN significantly enhances the effectiveness of chemo/immunotherapy in a ferroptosis-dependent manner in SMARCA4-deficient NSCLC. Collectively, our findings elucidate an intricate SMARCA4-ALDH16A1-TXN stability/function dual regulatory axis that governs ferroptosis and informs a therapeutic strategy for overcoming resistance to chemotherapy or immunotherapy in SMARCA4-deficient NSCLC.

DOI: https://doi.org/10.1038/s41467-025-63687-6
J Cell Mol Med. 2025 Sep;29(17): e70815

Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.

Yang Tian, Wei Li, Qing Zhai, Ying Yu, Jiaxin Yuan, Yan Ma, Jingjing Yang, Mingyue Li, Wenwen Chang, Wenjing Li, Keke Huang, Chongran Sun, Chen Zeng, Yingdi Sun, Jiabao Gu, Huilin Zhang, Dameng Li, Yanan Yu, Lu Hu, Peng Zhang, Bo Ma, Junnian Zheng, Pan Li, Feng Guo, Yang Sun.

  Protein S-palmitoylation, a dynamic and reversible post-translational modification involving the attachment of palmitate to cysteine residues, is a key regulator of protein functionality and cellular signalling. Dysregulation of this modification has emerged as a critical driver of cancer progression. Among the 23 DHHC palmitoyl transferases responsible for catalysing S-palmitoylation, aberrant expression of specific members is linked to tumorigenesis and development, underscoring their potential as promising therapeutic targets. However, the cancer-specific roles and substrates of individual DHHC enzymes remain poorly characterised. In this study, we identified DHHC9 as a crucial regulator of adenocarcinoma progression, including colorectal and lung cancers. Functional studies demonstrated that DHHC9 knockdown profoundly inhibited cell migration in vitro and tumour metastasis in vivo. Proteomic and functional analyses revealed that STRN4, a core component of the STRIPAK complex, was palmitoylated by DHHC9 at cysteine 701. The STRN4 palmitoylation reduced YAP phosphorylation, promoted nuclear translocation of YAP and activated downstream Hippo pathway transcriptional targets-including CCN1, CCN2 and ANKRD1-thereby driving cancer cell migration. Notably, we discovered two small molecules, Treprostinil and 10-HCPT, as potent DHHC9 inhibitors that effectively suppressed adenocarcinoma cell migration. Our findings define the DHHC9-STRN4-YAP axis as a novel mechanism linking palmitoylation to phosphatase regulation and Hippo pathway dysregulation, unveiling DHHC9 as a highly promising therapeutic target in cancer treatment.

Keywords:  STRN4 palmitoylation; ZDHHC9; adenocarcinoma metastasis; hippo pathway; palmitoylation inhibitors

DOI:  https://doi.org/10.1111/jcmm.70815
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01011-3. [Epub ahead of print]44(9): 116240

Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis.

Du Kong, Zhongbo Li, Sihua Zhao, Xueliang Yang, Jiadong Zheng, Yifan Guo, Wenyan Xu, Han Gao, Hanqing Guo, Qiang Zhang, Jian Zhu, Xianjue Ma, Bin Jin.

  Cell competition, an evolutionarily conserved quality control mechanism, selectively removes unfit or pre-malignant cells via cell-cell interactions. Through a genetic screen in Drosophila, we identify the phosphatase Pp1-87B as an essential regulator of JNK signaling crucial for eliminating scrib-deficient precancerous cells during tumor-suppressive cell competition. Mechanistically, impaired Pp1-87B activates JNK signaling via the Moe-Rho1 axis. Subsequently, JNK signaling acts as a central hub, integrating apoptosis and ferroptosis-like cell death by activating the Hippo signaling pathway. Critically, we demonstrate that the human ortholog, PPP1CC (protein phosphatase 1 catalytic subunit gamma), functions similarly to drive apoptosis and ferroptosis in human liver tumor cells through JNK activation. Collectively, our findings provide insights into the molecular integration of distinct cell death pathways during premalignant cell elimination in cell competition and identify PPP1CC as a promising therapeutic target for liver cancer treatment.

Keywords:  CP: Cancer; Drosophila; Hippo pathway; JNK pathway; PPP1CC; Pp1-87B; TSCC; ferroptosis; liver cancer; scrib; tumor-suppressive cell competition

DOI:  https://doi.org/10.1016/j.celrep.2025.116240
Am J Pathol. 2025 Aug 26. pii: S0002-9440(25)00300-1. [Epub ahead of print]

The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.

Dariusz Pytel, Jody Fromm Longo.

  Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Though genetically, clinically and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction due to their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.

Keywords:  Alzheimer’s Disease; Amyotrophic Lateral Sclerosis; ER stress; ERAD; Frontotemporal Dementia; Huntington’s Disease; Parkinson’s Disease; UPR; aggregates; autophagy; protein homeostasis; proteinopathies

DOI:  https://doi.org/10.1016/j.ajpath.2025.07.011