bims-scepro 2025-11-02 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–11–02
24 papers selected by
William Grey, University of York

Lnk Deficiency Enhances Translesion Synthesis to Alleviate Replication Stress and Promote Hematopoietic Stem Cell Fitness.
The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia.
Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.
Opening New Horizons: Advanced Hematopoietic Stem Cell Expansion Strategies Bridging Cord Blood Therapy from Bench To Bedside.
The systemic costs of hematopoietic stem cell aging.
Metformin induces ferroptosis associated with lipidomic remodeling in AML.
Intra-leukemic interferon signaling suppresses expansion and mediates chemoresistance in human AML.
A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
Targeting of SKP2 to combat drug resistance in multiple myeloma.
Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.
MNT: a new target for AML.
Structural dissection of αβ-tubulin heterodimer assembly and disassembly by human tubulin-specific chaperones.
Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.
Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML.
L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells.
Integration of a 4-gene risk score model enhances prognostic accuracy in acute myeloid leukemia.
Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging.
TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice.
Cell autonomous polarization by the planar cell polarity signaling pathway.
The histone methyltransferase MLL1 complex inhibits expression of fetal hemoglobin.
Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
Single-cell multiomics data integration and generation with scPairing.
CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage.
Origins of chromosome instability unveiled by coupled imaging and genomics.

J Clin Invest. 2025 Oct 30. pii: e191713. [Epub ahead of print]

Lnk Deficiency Enhances Translesion Synthesis to Alleviate Replication Stress and Promote Hematopoietic Stem Cell Fitness.

Brijendra Singh, Md Akram Hossain, Xiao Hua Liang, Jeremie Fages, Carlo Salas Salinas, Roger A Greenberg, Wei Tong.

  The adaptor protein LNK/SH2B3 negatively regulates hematopoietic stem cell (HSC) homeostasis. Lnk-deficient mice show marked expansion of HSCs without premature exhaustion. Lnk deficiency largely restores HSC function in Fanconi Anemia (FA) mouse models and primary FA patient cells, albeit protective mechanisms remain enigmatic. Here, we uncover a novel role for LNK in regulating translesion synthesis (TLS) during HSC replication. Lnk deficiency reduced replication stress-associated DNA damage, particularly in the FA background. Lnk deficiency suppressed single-strand DNA breaks, while enhancing replication fork restart in FA-deficient HSCs. Diminished replication-associated damage in Lnk-deficient HSCs occurred commensurate with reduced ATR-p53 checkpoint activation that is linked to HSC attrition. Notably, Lnk deficiency ameliorated HSC attrition in FA mice without exacerbating carcinogenesis during ageing. Moreover, we demonstrated that enhanced HSC fitness from Lnk deficiency was associated with increased TLS activity via REV1 and, to a lesser extent, TLS polymerase eta. TLS polymerases are specialized to execute DNA replication in the presence of lesions or natural replication fork barriers that stall replicative polymerases. Our findings implicate elevated use of these specialized DNA polymerases as critical to the enhanced HSC function imparted by Lnk deficiency, which has important ramifications for stem cell therapy and regenerative medicine in general.

Keywords:  Cell stress; DNA repair; Development; Hematology; Hematopoietic stem cells

DOI:  https://doi.org/10.1172/JCI191713
Blood. 2025 Oct 29. pii: blood.2025028918. [Epub ahead of print]

The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia.

Yuichiro Semba, Takuji Yamauchi, Daniel E Bauer, Seishi Ogawa, Koichi Akashi, Takahiro Maeda.

Acute myeloid leukemia (AML) with TP53 mutations is almost universally refractory to chemotherapy, molecular-targeted therapies, and hematopoietic stem cell transplantation, leading to dismal clinical outcomes. The lack of effective treatments underscores the urgent need for novel therapeutic strategies. Using genome-wide CRISPR/Cas9 dropout screens in isogenic Trp53-wild-type (WT) and knockout (KO) mouse AML models, combined with transcriptomic and proteomic analyses of mouse and human AML samples, we identify the XPO7 (exportin 7)-NPAT (nuclear protein, coactivator of histone transcription) pathway as essential for TP53-mutated AML cell survival. In TP53-WT AML, XPO7 functions as a tumor suppressor by regulating nuclear abundance of p53 protein, particularly when basal levels of functional p53 are high. However, in TP53-mutated AML, XPO7 drives leukemia proliferation by retaining NPAT, an XPO7-associated protein predominantly expressed in TP53-mutated AML, within the nucleus. NPAT depletion induces genome-wide histone loss, compromises genomic integrity, and triggers replication catastrophe in TP53-mutated AML cells. Notably, analysis of publicly available AML datasets, primary AML samples, and single-cell intra-patient mRNA profiles further reveals elevated XPO7 and NPAT expression in TP53-mutated AML. Finally, we validate the XPO7-NPAT pathway as a critical driver of leukemia progression in vivo using patient-derived xenograft (PDX) models of TP53-WT and TP53-mutant AML. Our study delineates key molecular mechanisms underlying TP53-mutated AML pathogenesis and identifies the XPO7-NPAT axis as a critical vulnerability in this refractory leukemia subtype.

DOI: https://doi.org/10.1182/blood.2025028918
Blood. 2025 Oct 27. pii: blood.2025029712. [Epub ahead of print]

Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.

Viktor Fetsch, Lennard Frederik Schwöbel, Ezgi Ozyerli-Goknar, Anna-Verena Stell, Marco Punta, Thomas Plenge, Tabea Klaus, Manoj K Gupta, Geoffroy Andrieux, Khalid Shoumariyeh, Sophie Pfeiffer, Eyleen Corrales, Lina Schlenke, Hosna Baniadam, Simon M Brandl, Massimo Andreis, Michal Remen, Alina Hartmann, Kathleen Grueter, Melissa Zwick, Natalie Köhler, Monika Kuban, Eric Metzger, Christoph Rummelt, Justus Duyster, Melanie Börries, Maike Hofmann, Julian Färber, Lukas M Braun, Alexander Zähringer, Michael Lübbert, Cristina Toffalori, Luca Vago, Florian H Heidel, Susana Minguet, Petya Apostolova, Tobias Feuchtinger, Kristina Maas-Bauer, Franziska Blaeschke, Michael W M Kühn, Marc Timmers, Tobias Wertheimer, Florian Perner, Robert Zeiser.

Acute myeloid leukemia (AML) carrying chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene frequently relapse after allogeneic hematopoietic cell transplantation (allo-HCT). Pharmacological blockade of the menin-KMT2A interaction disrupts the assembly of oncogenic KMT2A complexes on chromatin, thereby attenuating aberrant self-renewal and inducing myeloid differentiation. We found that beyond this anti-leukemic mechanism, menin-inhibition induced CIITA and MHC-II expression in KMT2A-rearranged and NPM1-mutated AML cells in vitro and in vivo. Increased MHC-II expression sensitized AML cells to T-cell mediated elimination after allo-HCT in mice. Menin-inhibition also increased MHC-II expression on primary human AML cells and enhanced the graft-versus-leukemia (GVL) effect in human xenograft models. Mechanistically, menin-inhibition increased expression of multiple human endogenous retroviruses (HERVs) leading to consecutive interferon-stimulated gene (ISG) upregulation and enhanced MHC-II expression. Additionally, menin-inhibition directly promoted anti-tumor effector functions of donor T-cells causing increased TNF-α, IFN-ү, perforin and granzyme A/B production and cytolytic activity. T-cell exhaustion and menin-KMT2A binding to genes encoding for negative regulators of T-cell activation were reduced by menin-inhibition. These findings indicate that menin-inhibition enhances the GVL-effect via the HERV/MHC-II axis in AML cells and promotes cytotoxicity of donor T-cells, which provides a rationale for a clinical trial using menin-inhibition as maintenance after allo-HCT.

DOI: https://doi.org/10.1182/blood.2025029712
Stem Cell Rev Rep. 2025 Oct 30.

Opening New Horizons: Advanced Hematopoietic Stem Cell Expansion Strategies Bridging Cord Blood Therapy from Bench To Bedside.

Guangzhao Li, Yunyan Zhao, Rongzhi Liu, Wei Du, Yu Zhang.

  Hematopoietic stem cell transplantation has been conducted in clinical settings to treat patients with malignant or non-malignant blood diseases for decades. Cord blood (CB) has been recognized as an essential graft source with beneficial characteristics, such as a lower risk of relapse and a lower rate of chronic graft-versus-host disease. However, the limited number of cells in CB impedes its broader use and hinders the ability to harness its benefits. Various expansion strategies have emerged to address this barrier, based on a deeper understanding of fate decisions and the maintenance of stemness in hematopoietic stem cells. To achieve an efficient transition from the laboratory to clinical application, several strategies have successfully managed scale-up manufacturing to satisfy clinically relevant requirements for both quality and scale. These approaches have progressed to the clinical stage and have demonstrated promising results. Novel expanded CB-derived hematopoietic stem and progenitor cells (HSPCs) therapies, including OMISIRGE (Omidubicel onlv.), Zemcelpro (Dorocubicel), and upcoming products with International Nonproprietary Name designations, introduce innovative concepts and comprehensive considerations for improving CB transplantation. This progress enables novel therapeutic options and represents a breakthrough in traditional CB transplants. In this context, we summarize and explore representative techniques and products to provide insights that inspire future developments in CB-derived HSPC therapies.

Keywords:  CB-derived HSPC therapy; Cord blood; Ex vivo expansion; Hematopoietic stem cell; Scale-up manufacturing

DOI:  https://doi.org/10.1007/s12015-025-10991-9
Development. 2025 Oct 15. pii: dev205103. [Epub ahead of print]152(20):

The systemic costs of hematopoietic stem cell aging.

Gayatri Puri, Roméo S Blanc.

  Stem cell behavior is tightly regulated by signals from the surrounding immune environment. Immune cells play an indispensable role in the maintenance, activation and differentiation of tissue-resident stem cells (TSCs). These interactions are dynamic and adapt across the lifespan, profoundly influencing regenerative capacity under both physiological and pathological conditions. Notably, immune dysfunction originating from aging hematopoietic stem cells (HSCs) disrupts tissue regeneration across distant organs, including the brain, muscle and skin. In this Review, we synthesize current knowledge on the interplay between HSC aging and TSC function, emphasizing how age-related changes in HSC-derived immune outputs impair local tissue homeostasis. We explore potential mechanisms underlying HSC-TSC communication, including inflammaging, cytokine signaling and the secretion of bioactive factors. Finally, we discuss emerging strategies aimed at rejuvenating aged HSCs, restoring immune equilibrium and enhancing systemic tissue regeneration. By linking systemic immune remodeling to local niche dysfunction, this Review proposes a hierarchical model in which HSC aging acts as a central regulator of tissue regenerative decline.

Keywords:  Bone marrow; Hematopoietic stem cell; Immunomodulation; Immunosenescence; Inflammation; Systemic aging

DOI:  https://doi.org/10.1242/dev.205103
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025016155. [Epub ahead of print]

Metformin induces ferroptosis associated with lipidomic remodeling in AML.

Dominique Sternadt, Diego A Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R Silveira, Albertus Tj Wierenga, Isabel Weinhäuser, Shanna M Hogeling, Lieve Oudejans, Pilar Casares-Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A Huls, Lynn Quek, Jan Jacob Schuringa.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025016155
Blood Cancer Discov. 2025 Oct 30.

Intra-leukemic interferon signaling suppresses expansion and mediates chemoresistance in human AML.

Daiki Karigane, Amy C Fan, Toshinobu Nishimura, Kensuke Kayamori, Yusuke Nakauchi, Thomas Köhnke, Athreya Rangavajhula, Asiri Ediriwickrema, Brooks A Benard, Rozario Thomas, Feifei Zhao, Melissa Stafford, Fabian P Suchy, Jonas L Fowler, Mark P Chao, Tian Yi Zhang, Kyle M Loh, Hiromitsu Nakauchi, Ravindra Majeti.

Intra-tumoral heterogeneity can impact the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse. While the role of cell-extrinsic factors has been described for AML relapse, whether interactions between cancer cells affects chemoresistance is not fully known. Here, we demonstrated that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. This suppression is mediated in part by both type I and type II intra-leukemic interferon (IFN) signaling and dependent on BST2. Importantly, blocking antibodies to type II IFN receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting IFN signaling as a potential therapeutic target to counter chemoresistance.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0173
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496

A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.

Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.

  Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116496
Sci Rep. 2025 Oct 29. 15(1): 37838

Targeting of SKP2 to combat drug resistance in multiple myeloma.

Omar Faruq, Jane Ngo, Deepak Iyer, Jonahunnatha Nesson, Mariusz Shrestha, Hong Chang.

  Multiple myeloma (MM) is an incurable plasma cell malignancy in which drug resistance remains a significant limitation to treatment. SKP2, the substrate-recognition component of the SCF-SKP2 ubiquitin-protein ligase complex, plays a critical role in the progression of various cancers, including MM. Targeting SKP2 as a therapeutic strategy offers a promising avenue for combating drug resistance in myeloma. Here, we show that SKP2 expression increases as the disease progresses from pre-myeloma to newly diagnosed and relapsed stages. Gene set enrichment analysis (GSEA) and immunoblotting further revealed that SKP2 inhibition by the preclinical chemical inhibitor SkpinC1 leads to decreased STAT3 inflammatory signalling and c-MYC expression in myeloma cells. When tested in SKP2-overexpressing cells, SkpinC1 retained the ability to reduce activated STAT3, c-MYC, and c-MAF protein levels to impair cell growth and induce apoptosis. Furthermore, SkpinC1 synergistically enhanced the sensitivity of patient myeloma samples to bortezomib. Taken together, these findings underline the potential of SKP2 inhibition to overcome drug resistance in MM.

Keywords:   SKP2 (S-phase kinase 2); Drug resistance; Multiple myeloma; STAT3; c-MAF; c-MYC

DOI:  https://doi.org/10.1038/s41598-025-21719-7
Exp Hematol Oncol. 2025 Oct 28. 14(1): 127

Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.

Raphael Hablesreiter, Paulina M Strzelecka, Klara Kopp, Natalia Estrada, Anna Dolnik, Marlon Tilgner, Coral Fustero-Torre, Felicitas Thol, Florian H Heidel, Michael Heuser, Laleh Haghverdi, Lars Bullinger, Friederike Christen, Frederik Damm.

  Reconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies.

Keywords:  AML; CBF; Clonal evolution; Clonal heterogeneity; Intra-tumor heterogeneity; Single-cell DNA sequencing

DOI:  https://doi.org/10.1186/s40164-025-00718-4
Blood Neoplasia. 2025 Nov;2(4): 100149

MNT: a new target for AML.

Karla C Fischer, Veronique Litalien, Sarah T Diepstraten, Michelle Jahja, Fiona C Brown, Gemma L Kelly, Andrew H Wei, Suzanne Cory.

Deregulated expression of the transcription factor c-MYC is well established as a primary driver of diverse tumor types. In this study, for the first time to our knowledge, we show that mouse and human myeloid leukemias provoked by oncogenic mixed lineage leukemia (MLL) fusion proteins are dependent on the MYC family member MNT (MAX network transcriptional repressor), which is highly expressed in these AMLs. To investigate the role of MNT, we generated Mnt-deletable murine MLL::AF9 acute myeloid leukemias (AMLs), using the well-studied hemopoietic reconstitution model. Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Remarkably, by inducing Mnt deletion in vivo in transplanted MLL::AF9 AMLs, we significantly extended the survival of transplant recipients (P < .0001), 50% of which became leukemia free. Using inducible CRISPR/Cas9, we also showed that 3 of 4 human AML cell lines were more potently killed in vitro by BH3 mimetic drugs after MNT deletion. Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.

DOI: https://doi.org/10.1016/j.bneo.2025.100149
Science. 2025 Oct 30. 390(6772): eady2708

Structural dissection of αβ-tubulin heterodimer assembly and disassembly by human tubulin-specific chaperones.

Yeonjae Seong, Hyunmin Kim, Kyumi Byun, Yeon-Woo Park, Soung-Hun Roh.

Microtubule assembly requires a set of chaperones known as tubulin-binding cofactors (TBCs). We used cryo-electron microscopy to visualize how human TBCD, TBCE, TBCC, and guanosine triphosphatase (GTPase) Arl2 mediate αβ-tubulin assembly and disassembly. We captured multiple conformational states, revealing how TBCs orchestrate tubulin heterodimer biogenesis. TBCD stabilizes monomeric β-tubulin and scaffolds the other cofactors. Guanosine triphosphate (GTP) binding to Arl2 induces conformational changes that toggle the complex between assembly and disassembly. TBCD and TBCE guide α- and β-tubulin into a partially assembled interface, and TBCC, acting as a molecular clamp, completes the heterodimer. TBCD also functions as a GTPase activating protein for β-tubulin. β-tubulin GTP hydrolysis is coupled to Arl2's GTPase activity, establishing a checkpoint that ensures that only fully matured heterodimers proceed. These findings provide a structural framework for tubulin heterodimer biogenesis and recycling, supporting cytoskeletal proteostasis.

DOI: https://doi.org/10.1126/science.ady2708
Nat Biotechnol. 2025 Oct 30.

Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.

Karin Gustafsson, Sergey Isaev, Kamdin Mirsanaye, Johanna Hofmann, Kameron A Kooshesh, Ninib Baryawno, Anna Kiem, Nicolas Severe, Ting Zhao, Elizabeth W Scadden, Joel A Spencer, Christian Burns, Kumaran Akilan, Nikolaos Barkas, Hayalneh Gessessew, Konstantinos D Kokkaliaris, Charles P Lin, Peter V Kharchenko, David T Scadden.

Thymic atrophy and the progressive immune decline that accompanies it is a major health problem, chronically with age and acutely with immune injury. No definitive solution is available. Here we demonstrate that one of the three mesenchymal cell subsets identified by single-cell analysis of human and mouse thymic stroma is a critical niche component for T lymphopoiesis. The Postn+ subset is perivascular, and its depletion abrogates T cell progenitor recruitment, likely through production of the chemokine Ccl19. It markedly declines with age and in the acute setting of hematopoietic stem cell transplant conditioning. When isolated and adoptively transferred, Postn+ cells durably engraft the atrophic thymus, recruit early T progenitors, increase T cell neogenesis and enhance T cell response to vaccination. More readily available mesenchymal populations expressing Ccl19 provide similar effects. These data define a thymus lymphopoietic niche cell type that may be manipulated therapeutically to regenerate T lymphopoiesis.

DOI: https://doi.org/10.1038/s41587-025-02864-w
Blood. 2025 Oct 27. pii: blood.2025030558. [Epub ahead of print]

Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML.

Bogdan Popescu, Matthew F Jones, Madison Piao, Elaine Tran, Andrew Koh, Isabelle Lomeli, Cheryl A C Peretz, Natalia Murad, Sydney Abelson, Carolina E Morales, Jose M Rivera, Alexa Rane Batingana, Jeevitha D'Souza, Yana Pikman, Michael L Cheng, Aaron C Logan, Benjamin J Huang, Elliot Stieglitz, Catherine C Smith.

Aberrant activation of RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FLT3-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, including the BCL2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multi-selective inhibitor of GTP-bound active [RAS(ON)] isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and pro-apoptotic activity across AML cell lines with MAPK-activating signaling mutations. In cell line models with acquired FLT3i resistance due to secondary RAS mutations, treatment with RMC-7977 restored sensitivity to FLT3i. Similarly, RMC-7977 effectively reversed resistance to venetoclax in RAS-addicted cell line models with both RAS wild-type and mutant genetic backgrounds. In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling.

DOI: https://doi.org/10.1182/blood.2025030558
Stem Cell Res Ther. 2025 Oct 31. 16(1): 599

L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells.

Cai-Xia Dou, Hao-Zhan Qu, Ying-Chao Qin, Xiao-Fan Wang, Jia-Yi Zhou, Xiu-Qi Wang, Hui-Chao Yan.

BACKGROUND: Intestinal stem cells (ISCs) sustain epithelial homeostasis through rapid mitochondrial metabolism, however, how they sense nutrient signals to regulate mitochondrial function remains unclear.
METHODS: We examined the role of L-glutamate (Glu) in regulating cell mitochondrial biosynthesis using in vivo piglets, ex vivo porcine intestinal organoids (IOs), and in vitro IPEC-J2 cells.
RESULTS: Glu enhanced jejunal development in weaned piglets. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis revealed the significant enrichment of mitochondrial functions and activation of EGFR-MEK-ERK-mTFB2 signaling pathway in the jejunum. In vitro, 5 mM Glu promotes mitochondrial biosynthesis and potentiates the EGFR-MEK-ERK-mTFB2 axis. Whereas inhibition of EGFR with Osimertinib and silencing EGFR abolished these effects in IOs and IPEC-J2 cells. Colocalization and biochemical studies demonstrated interaction between Glu and EGFR in IOs.
CONCLUSIONS: Glu promotes mitochondrial biogenesis and ISC expansion by activating the EGFR-MEK-ERK-mTFB2 axis, highlighting a nutrient-sensing mechanism that couples energy availability to ISC function.

DOI: https://doi.org/10.1186/s13287-025-04718-3
Cell Cycle. 2025 Oct 29. 1-17

Integration of a 4-gene risk score model enhances prognostic accuracy in acute myeloid leukemia.

Yiqing Li, Boqi Li, Jie Xiao, Kezhi Huang, Yuchan Liang, Peiting Zeng, Wenjuan Yang, Danian Nie.

  The clinical outcomes of acute myeloid leukemia (AML) patients exhibit substantial heterogeneity, with relapse posing a formidable challenge. Herein, we developed a risk score model by integrating relapse-related genes through Cox regression analysis. The relapse-related genes were identified via differential gene expression analysis of 15 matched diagnosed and relapsed AML samples retrieved from the Gene Expression Omnibus (GEO) database. These genes include SCN9A, CFH, CD34, and CALCRL. Our findings demonstrate that higher risk scores were significantly associated with an unfavorable ELN2017 risk classification, leukemic transformation, as well as FLT3-ITD and RUNX1 mutations. Conversely, lower risk scores were linked to NPM1 mutation. Patients with higher risk scores had a shorter overall survival (OS). Furthermore, we integrated the risk score model with the European LeukemiaNet (ELN) risk classification to establish a novel composite risk classification scheme. Patients were classified into three new risk groups based on composite risk classification showing significantly distinct OS. In summary, the four-gene risk score holds promise in predicting the OS of AML patients, and the composite risk classification shows greater potential in predicting the outcomes of AML patients. These four genes may represent potential therapeutic targets in the treatment of AML.

Keywords:  Acute myeloid leukemia; European LeukemiaNet; bioinformatics; relapse; risk score

DOI:  https://doi.org/10.1080/15384101.2025.2578389
Stem Cell Res Ther. 2025 Oct 27. 16(1): 580

Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging.

Mathilde Brulé, Anais Horochowska, Emeline Fontaine, Raoul Torero-Ibad, Flavie Woesteland, Marie Denoulet, Jean Pesez, Eric Adriaenssens, Robert-Alain Toillon, Xuefen Le Bourhis, Benjamin Pfeuty, Chann Lagadec, François Anquez.

   BACKGROUND: Phenotypic plasticity is a major factor in tumor heterogeneity and treatment resistance. In particular, cancer stem cells (CSCs) represent a small subpopulation within tumors that possesses self-renewal and tumor-forming capabilities. Understanding reprogramming, maintenance, and lineage properties of CSCs requires dedicated tools to disentangle the respective influences of phenotypic inheritance and cell-cell interactions.
METHODS: Here, we set up ultra-wide field microscopy to image breast cancer cell lines expressing a stemness fluorescent reporter over several days. The fluorescent reporter distinguishes three phenotypes: CSCs, cancer differentiated cells (CDCs), and intermediate/transiting cancer cells (iCCs).
RESULTS: Spatial statistics indicate significant zonation in which CSCs cluster together and are spatially separated from CDCs, forming patterns resembling niches. Surprisingly, single-cell time series reveal spontaneous reprogramming events from CDC to CSC even in unperturbed populations. We identify that such transitions are prone to arise during the cell cycle. Moreover, lineage analysis shows that the phenotype is partially inherited from ancestor cells. However, such heredity is not sufficient to explain the spatial properties of the cell population, which also depend on cell-cell interactions. Indeed, we find that phenotypic transitions of cancer cells are influenced by the phenotypic state of neighboring cells. Reprogramming into CSCs is respectively promoted and inhibited by the presence of CSCs and CDCs in the neighborhood.
CONCLUSIONS: Altogether, our results disentangle how phenotypic inheritance and intercellular interactions orchestrate the spatio-temporal self-organization of cancer cell heterogeneity, maintaining a subpopulation of CSCs within niches.

Keywords:  Cancer stem cells; Plasticity; Single cell tracking; Time-lapse microscopy

DOI:  https://doi.org/10.1186/s13287-025-04681-z
Haematologica. 2025 Oct 30.

TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice.

Lei Zhang, Wenyan Li, Rohit Thalla, Rongyao Ma, Ryan Mack, Ameet R Kini, Austin Runde, Patrick A Hagen, Kevin Barton, Jorgena Kosti-Schwartz, Peter Breslin, Hong-Long Ji, Jiwang Zhang.

Mutant SF3B1 (SF3B1mut) in hematopoietic stem/progenitor cells (HSPCs) primarily affects erythropoiesis, resulting in myelodysplastic syndromes (MDS) with refractory macrocytic anemia and ring sideroblasts. SF3B1mut results in aberrant splicing of a large number of transcripts in HSPCs due to the alternative use of cryptic splice sites. Aberrant splicing of Tmem14c and Abcb7 has been shown to be the cause of the ring sideroblasts. However, the key mis-spliced gene(s) that drive macrocytic anemia have not been well-determined. Mis-splicing and downregulation of TAK1 pre-mRNA was detected in SF3B1mut-HSPCs. We found that TAK1 is required for the survival of HSPCs by restricting RIPK1 dependent and independent PANoptosis. PANoptosis was increased in bone marrow samples from SF3B1mut-MDS patients. To study whether TAK1-downregulation is the cause of anemia in SF3B1mut-MDS, we knocked down Tak1 (Tak1KD) in mouse HSPCs. We found that mice transplanted with Tak1KD-HSPCs developed anemia and that Ripk1 inhibition could restore blood cell counts in such anemic mice. Tak1KD-HSPCs are highly sensitive to TAK1 inhibitor- or cIAP inhibitor-induced PANoptosis. Furthermore, RIPK1 inhibition could also correct differentiation and survival defects of SF3B1mut human erythroblasts (EBs). TAK1 inhibitor could also preferentially eliminate SF3B1mut HSPCs from MDS patient samples. Our study suggests that SF3B1mut MDS can be treated by either inhibition of RIPK1-PANoptotic signaling to restore blood cell counts or activation of PANoptosis to eliminate the mutant HSPCs.

DOI: https://doi.org/10.3324/haematol.2025.287951
Nat Commun. 2025 Oct 28. 16(1): 9503

Cell autonomous polarization by the planar cell polarity signaling pathway.

Alexis T Weiner, Silas Boye Nissen, Kaye Suyama, Bomsoo Cho, Gandhy Pierre-Louis, Jeffrey D Axelrod.

As epithelial cells polarize in the tissue plane, the Planar Cell Polarity (PCP) signaling module segregates two distinct molecular subcomplexes to opposite sides of cells. Homodimers of the atypical cadherin Flamingo form bridges linking opposite complexes in neighboring cells, coordinating their direction of polarization. Feedback is required for cell polarization, but whether feedback requires intercellular and/or intracellular pathways is unknown. Using novel tools, we show that cells lacking Flamingo, or bearing a homodimerization-deficient Flamingo, polarize autonomously, indicating that functional PCP subcomplexes form and segregate cell-autonomously. Furthermore, we identify feedback pathways and propose an asymmetry amplifying mechanism that operate cell-autonomously. The intrinsic logic of PCP signaling is therefore more similar to that in single cell systems than was previously recognized.

DOI: https://doi.org/10.1038/s41467-025-64563-z
J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02715-2. [Epub ahead of print] 110863

The histone methyltransferase MLL1 complex inhibits expression of fetal hemoglobin.

Yufen Han, Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Kartik R Roy, John Tisdale, Yang Du.

  Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. Moreover, treatment of CD34+ HSPCs from SCD patients with MENIN inhibitors substantially increased γ-globin expression in their erythroid progenies. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and β-thalassemia.

Keywords:  Men1; chromatin regulation; differentiation; hemoglobin; transcription regulation

DOI:  https://doi.org/10.1016/j.jbc.2025.110863
Nat Cell Biol. 2025 Oct 31.

Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.

Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.

The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.

DOI: https://doi.org/10.1038/s41556-025-01799-3
Cell Rep Methods. 2025 Oct 27. pii: S2667-2375(25)00247-4. [Epub ahead of print] 101211

Single-cell multiomics data integration and generation with scPairing.

Jeffrey Niu, Carlos Vasquez-Rios, Jiarui Ding.

  Single-cell multiomics technologies generate paired measurements of different cellular modalities, such as gene expression and chromatin accessibility. However, multiomics technologies are more expensive than their unimodal counterparts, resulting in smaller and fewer available multiomics datasets. Here, we present scPairing, a deep learning model inspired by contrastive language-image pre-training (CLIP), which embeds different modalities from the same single cells onto a common embedding space. We leverage the common embedding space to generate novel multiomics data following bridge integration, a method that uses an existing multiomics bridge to link unimodal data. Through extensive benchmarking, we show that scPairing constructs an embedding space that fully captures both coarse and fine biological structures. We then use scPairing to generate new multiomics data from retina, immune, and renal cells. Furthermore, we extend scPairing to generate trimodal data. The generated multiomics datasets can facilitate the discovery of novel cross-modality relationships and the validation of existing biological hypotheses.

Keywords:  CITE-seq; CP: computational biology; CP: systems biology; contrastive learning; deep generative models; scATAC-seq; scRNA-seq; single-cell multiomics; variational autoencoders

DOI:  https://doi.org/10.1016/j.crmeth.2025.101211
Leukemia. 2025 Oct 27.

CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage.

T Benz, P Larghero, C Meyer, T Hanewald, D Brüggmann, A-E Hentrich, F Louwen, R Marschalek.

The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.

DOI: https://doi.org/10.1038/s41375-025-02791-4
Nature. 2025 Oct 29.

Origins of chromosome instability unveiled by coupled imaging and genomics.

Marco Raffaele Cosenza, Alice Gaiatto, Büşra Erarslan Uysal, Álvaro Andrades, Nina Luisa Sautter, Marina Simunovic, Michael Adrian Jendrusch, Sonia Zumalave, Tobias Rausch, Aliaksandr Halavatyi, Eva-Maria Geissen, Joshua Lucas Eigenmann, Thomas Weber, Patrick Hasenfeld, Eva Benito, Catherine Stober, Isidro Cortes-Ciriano, Andreas E Kulozik, Rainer Pepperkok, Jan O Korbel.

Somatic chromosome instability results in widespread structural and numerical chromosomal abnormalities (CAs) during cancer evolution1-3. Although CAs have been linked to mitotic errors resulting in the emergence of nuclear atypia4-7, the underlying processes and rates of spontaneous CA formation in human cells are underexplored. Here we introduce machine-learning-assisted genomics and imaging convergence (MAGIC)-an autonomously operated platform that integrates live-cell imaging of micronucleated cells, machine learning on-the-fly and single-cell genomics to systematically investigate CA formation. Applying MAGIC to near-diploid, non-transformed cell lines, we track de novo CAs over successive cell cycles, highlighting the common role of dicentric chromosomes as initiating events. We determine the baseline CA mutation rate, which approximately doubles in TP53-deficient cells, and observe that chromosome losses arise more frequently than gains. The targeted induction of DNA double-strand breaks along chromosome arms triggers distinct CA processes, revealing stable isochromosomes, coordinated segregation and amplification of isoacentric segments in multiples of two, as well as complex CA outcomes, influenced by the chromosomal break location. Our data contrast de novo CA spectra from somatic mutational landscapes after selection occurred. The experimentation enabled by MAGIC advances the dissection of DNA rearrangement processes, shedding light on fundamental determinants of chromosomal instability.

DOI: https://doi.org/10.1038/s41586-025-09632-5