bims-scepro 2026-10-11 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–10–11
fifteen papers selected by
William Grey, University of York

Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.
Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment.
Loss of Tars induces proteostasis stress and drives HSPC exhaustion through mTORC1 activation.
Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation.
Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.
KT-253, a highly potent and selective MDM2 protein degrader, eliminates malignant myelofibrosis stem/progenitor cells.
Monocyte Galectin-9 is associated with CD8⁺ T-cell dysfunction and early relapse after haploidentical hematopoietic stem cell transplantation.
A platform of serially transplantable AML PDX models covering subgroups for which no cell lines exist.
Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML.
Neutrophil-derived S100A8/A9 is associated with inflammation that supports Dnmt3a-mutant hematopoiesis.
IMiD/CELMoD resistance in myeloma is associated with changes in lipid metabolism that may be targetable.
Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
Recombinant hematopoietic growth factors in acute myeloid leukemia.
Novel RNA polymerase I and cyclin-dependent kinase combination therapy for the treatment of aggressive acute myeloid leukemia.
Prediction of Oxidative Stress- and Anticancer Drug-Induced Cellular Senescence Using Holotomography and Interpretable Attention-Based Contrastive Learning.

Nat Commun. 2026 09 05. pii: 10558. [Epub ahead of print]17(1):

Suppressing glutamate dehydrogenase guides hematopoietic stem cell divisions into self-renewal.

Michihiro Hashimoto, Michie Uchikawa, Yuichiro Arima, Akiyasu Iwase, Ayano Yahagi, Mizuki Ishimaru, Tomomasa Yokomizo, Ayako Nakamura-Ishizu, Yosuke Tanaka, Kenichi Miharada, Hiroki Kurihara, Goro Sashida, Toshio Suda, Terumasa Umemoto.

Hematopoietic stem cells (HSCs) self-renew to expand their pool but often differentiate upon division. Thus, it remains unclear how HSCs maintain their stemness during or after division. Here, we show that the suppression of glutamate dehydrogenase (Glud1), a key enzyme responsible for glutamate (Glu) catabolism, supports the maintenance of HSCs during division. We find that self-renewing mouse HSCs during hematopoietic regeneration exhibited lower intracellular Glu levels compared to HSCs differentiating during ex vivo culture. We therefore focus on the negative regulation of Glu catabolic reactions as a candidate factor to maintain HSCs during division, and find that treatment with the Glud1 inhibitor, R162, maintains a subset of HSCs that would otherwise differentiate during division under normal culture conditions. This treatment successfully results in an approximately 500-fold expansion of functional mouse HSCs that maintain expression pattern of conventional stem cell markers over a 30-day culture period. Importantly, this positive effect of Glud1 inhibition is independent of suppressing cell divisions and dependent on robust JAK2-STAT signaling. Overall, our findings propose that Glud1 inhibition, coupled with robust JAK2-STAT signaling, characterizes a functional HSC state during division, enabling ex vivo expansion of mouse HSCs under conventional culture conditions.

DOI: https://doi.org/10.1038/s41467-026-77151-6
EMBO Mol Med. 2026 Oct 09.

Activated protein C promotes hematopoietic stem and progenitor cell quiescence and engraftment.

Simon J Pöllmann, Marcel G E Rommel, Leal Oburoglu, Tanja Hirch, Fabiola Valdivia-Francia, Kah Mun Siow, Timon Menzi, Julia Ackva, Franziska Schenk, Matthias J Neeracher, Ataman Sendoel, Janine Reichenbach, E Camilla Forsberg, Ute Modlich.

Hematopoietic stem cells (HSCs) are the definitive source of all blood cells and replenish them for life. The endothelial protein C receptor (EPCR) which signals via its coreceptor protease-activated receptor 1 (PAR1) is expressed on a subpopulation of highly quiescent HSCs with high engraftment potential after transplantation. We demonstrate that EPCR/PAR1 on human CD34+ hematopoietic stem and progenitor cells (HSPCs) can be activated by both thrombin (THR) and activated protein C (aPC), inducing distinct signaling. PAR1 activation by THR in HSPCs led to Ca2+ flux, phosphorylation of CREB and ERK1/2 and increased glycolysis. In contrast, aPC activated CREB and AKT, but not ERK1/2, Ca2+ flux or metabolic changes. Functionally, stimulation of human CD34+ cells with aPC decreased differentiation and enhanced clonogenic potential. aPC counteracted the enforced proliferation of HSPCs by interleukin 1α in vitro. Short stimulation of CD34+ cells with aPC enhanced their short-term serial engraftment in immunodeficient mice. Our findings identify aPC/PAR1 signaling as a key target supporting CD34+ HSPC maintenance, stress resistance and regeneration, while THR/PAR1 signaling has opposing effects.

DOI: https://doi.org/10.1038/s44321-026-00529-y
Acta Pharmacol Sin. 2026 Oct 08.

Loss of Tars induces proteostasis stress and drives HSPC exhaustion through mTORC1 activation.

Ning-Zhe Li, Meng-Ke He, Qiang Wang, Na Liu, Zi-Xuan Wang, Ming-Kang Qi, Yi Chen, Ru-Fang Xiang, Yu-Ting Dai, Fan Zhang.

  Hematopoietic stem and progenitor cells (HSPCs) rely on tightly regulated proteostasis to preserve their self-renewal and differentiation potential throughout life. However, how proteostasis stress induced by translational dysregulation affects HSPC homeostasis remains poorly understood. Here, we found that knockout of the cytoplasmic threonyl-tRNA synthetase (Tars), which is a component of the translation machinery, caused HSPC exhaustion and definitive, but not primitive, hematopoiesis defects in zebrafish. Similarly, TARS functional deficiency resulted in human CD34+ HSC exhaustion and a decrease in colony-forming unit-granulocyte, macrophage (CFU-GM) and colony-forming unit-macrophage (CFU-M) numbers while sparing burst-forming unit-erythroid (BFU-E) numbers in vitro. Functional rescue experiments demonstrated that the enzymatic activity of Tars is indispensable for HSPC maintenance and definitive hematopoiesis. Interestingly, these phenotypes occurred prior to the apparent decrease in global protein translation and were independent of global translation inhibition, hinting that these defective HSPCs were eliminated by an unknown mechanism. Transcriptomic and proteomic profiling revealed that Tars deletion caused widespread proteomic reprogramming and mTORC1 signaling activation, whereas pharmacological or genetic inhibition of mTORC1 partially rescued HSPC exhaustion in tars-/- embryos. These findings uncover a link between translational machinery integrity, mTORC1 signaling, and HSPC fate determination, providing critical insight into how proteostasis stress is sensed and resolved to maintain hematopoietic homeostasis.

Keywords:  Zebrafish; hematopoietic stem and progenitor cells; mTORC1; proteostasis; threonyl-tRNA synthetase

DOI:  https://doi.org/10.1038/s41401-026-01946-y
JCI Insight. 2026 Oct 08. pii: e199771. [Epub ahead of print]11(19):

Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation.

Cuiping Zhang, Xia Yao, Pinpin Sui, Liming Hou, Bowen Yan, Larry L Luchsinger, Gang Huang, Sheng Tong, Youwen Zhang, Bojing Shao, Hong Qian, Hong Zheng, Hui Zhong, Feng-Chun Yang, Ying Liang.

  Acute myeloid leukemia (AML) is the most common adult leukemia diagnosis. Bone marrow (BM) niche significantly influences the initiation and progression of AML. However, our knowledge about the effect of leukemic niche on leukemia stem cells (LSC) and leukemogenesis is limited. In this study, we identified an extrinsic-regulatory function of latexin (Lxn) in leukemogenesis. Using a MLL-AF9-induced AML mouse model in WT and Lxn-KO (Lxn-/-) recipient mice, we found that Lxn deletion in the BM niche enhanced the survival of AML mice by suppressing LSCs and reducing blood blasts. Single-cell RNA-seq of stromal cells and cell communication analysis uncovered downregulation of the leukemia inhibitory factor receptor (LIFR) signaling pathway in the Lxn-/- niche, particularly within mesenchymal stromal cells (MSCs). Mechanistically, reduced LIFR level in Lxn-/- MSCs upregulated Cxcl9 expression, leading to increased recruitment of CD8 T cells and enhanced cytotoxicity against leukemic cells. Combination of Lxn niche deletion and immune checkpoint inhibitor PD-1 further prolonged survival. The findings have important clinical implications, suggesting that Lxn inhibition could improve the efficacy of AML therapies by targeting the leukemia niche and enhancing immune surveillance.

Keywords:  Hematology; Leukemias; Oncology

DOI:  https://doi.org/10.1172/jci.insight.199771
Cancer Lett. 2026 Oct 04. pii: S0304-3835(26)00630-0. [Epub ahead of print] 218866

Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.

Maddalena Benetton, Ambra Da Ros, Alberto Peloso, Giorgia Longo, Sara Perpinello, Chiara Frasson, Tiago Branco Fonseca, Elena Varotto, Silvia Bresolin, Claudia Tregnago, Luca Scorrano, Benjamin J Huang, Soheil Meshinchi, Franco Locatelli, Martina Pigazzi.

  Standard chemotherapy effectively induces complete remission in most children with acute myeloid leukemia (AML), however relapse remains the main cause of treatment failure. Leukemia stem cells (LSCs) are proposed to constitute a therapy-resistant reservoir driving disease recurrence, but their reliable identification remains unresolved. We explored intracellular reactive oxygen species (ROS) levels in pediatric AML at diagnosis and sorted ROS-low (RL) and ROS-high (RH) cell fractions. We found that RL cells exhibited increased quiescence, sustained serial colony-forming capacity and engraftment in mice when compared to the RH fraction. Moreover, in a 3D niche model, RL cells preferentially localized to hypoxic regions and were resistant to cytarabine, altogether indicating enrichment for functional LSCs. Transcriptomic analyses revealed enrichment of stemness, adhesion and niche-interaction programs in RL cells, alongside downregulation of mitochondrial and oxidative phosphorylation pathways. Consistently, RL cells displayed reduced oxygen consumption and ATP production, together with remodeled cristae structure despite preserved mitochondrial mass. Paradoxically, complex I inhibition selectively impaired RL cell viability, indicating a dependency on oxidative phosphorylation. Using RL transcriptome, we derived a gene signature that, when applied to single-cell RNA-sequencing data of pediatric AML cases, identified LSCs within the bulk regardless of differentiation status, and showed significant prognostic value. Finally, transcriptional program trajectory indicated that RL fraction contributed to generate the whole AML bulk, whereas gene mutations were maintained in RL and RH cells. Overall, this ROS-based strategy represents a new tool to isolate stem cells transcending traditional markers, and identifies novel clinically relevant vulnerabilities to target LSCs.

Keywords:  cell adhesion; gene signatures; leukemia stem cells; mitochondria; pediatric acute myeloid leukemia; reactive oxygen species; transcriptomics

DOI:  https://doi.org/10.1016/j.canlet.2026.218866
Leukemia. 2026 Oct 06.

KT-253, a highly potent and selective MDM2 protein degrader, eliminates malignant myelofibrosis stem/progenitor cells.

Min Lu, Lijuan Xia, Yogesh Chutake, Joyoti Dey, Ronald Hoffman.

Approximately 96% of myelofibrosis (MF) patients express wild-type (WT) p53. MF hematopoietic stem/progenitor cells (HSPCs) overexpress MDM2 that degrades WTp53, thereby supporting MF HSPC survival. Although MDM2 small-molecule inhibitors (SMIs) are clinically effective, their benefit is compromised by an inability to sufficiently deplete MF HSPCs. KT-253 degrades MDM2 and overcomes the p53-dependent feedback loop that restores MDM2 levels observed with the use of MDM2 SMIs such as AMG-232. We evaluated the effects of KT-253 using MPN cell lines, primary MF CD34+ cells, and a mouse xenograft model. KT-253 activity was correlated with activation of the p53 pathway and upregulation of p53 downstream genes, including p21, NOXA, and PUMA in WTp53 UKE-1 cells but not p53 mutant cells. KT-253 treatment induced apoptosis of primary MF CD34+ cells at a tenfold lower concentration than AMG-232 and prevented the upregulation of MDM2 seen with AMG-232. Low doses of KT-253 reduced total MF colony and JAK2V617F+ colony numbers to a far greater extent than log-higher doses of AMG-232 (60% and 71% versus 20% and 10%, respectively). Mouse xenograft studies indicated that KT-253 more effectively depleted JAK2V617F+ MF marrow-repopulating cells. These findings support the further clinical evaluation of MDM2 degraders for the treatment of MF patients.

DOI: https://doi.org/10.1038/s41375-026-03163-2
Biomark Res. 2026 Oct 07. pii: 132. [Epub ahead of print]14(1):

Monocyte Galectin-9 is associated with CD8⁺ T-cell dysfunction and early relapse after haploidentical hematopoietic stem cell transplantation.

Weiqian Dai, Xueying Zhao, Linjie Wu, Aiming Pang, Lisha Wang, Shihui Ma, Chaofan Geng, Shiyang Wang, Xinhui Zheng, Fang Dong, Linping Hu, Erlie Jiang, Tao Cheng, Sha Hao.

   BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) stands as a leading curative approach for AML in China. However, relapse remains a major challenge for patient survival, often occurring within six months post-transplant and associated with a five-year mortality rate of up to 80%. Here, we characterized early immune reconstitution after haplo-HSCT and investigated immune features associated with early relapse (ER) in AML.
METHODS: We analyzed two clinical cohorts: patients with AML (n = 44) and aplastic anemia (AA; n = 38), and AML patients with continuous complete remission (CCR, n = 55) versus ER (n = 38). Single-cell RNA sequencing was performed on longitudinal peripheral blood and bone marrow samples from AML and AA patients (n = 3 and 4), while single-cell RNA/TCR sequencing was performed on bone marrow samples from CCR and ER patients (n = 3 each). Flow cytometry assessed monocyte Galectin-9 surface expression and CD8⁺ T-cell phenotypes. Galectin-9-associated monocyte-T-cell interactions and the effects of the TIM-3 inhibitor MG-T-19 were evaluated in vitro and in a murine AML model.
RESULTS: AML and AA patients showed different patterns of early immune reconstitution after haplo-HSCT, including differences in monocyte and T-cell recovery. Within AML, ER patients exhibited increased T-cell representation but reduced basal TNF-α expression and altered exhaustion-associated CD8⁺ T-cell phenotypes before relapse. Monocytes represented a prominent Galectin-9-expressing compartment, and surface Galectin-9 on monocytes was elevated in ER compared with CCR patients as early as day 30 post-transplantation. Exogenous Galectin-9 induced dose-dependent functional and exhaustion-associated changes in CD8⁺ T cells, while Galectin-9-high IFN-conditioned monocytes impaired CD8⁺ T-cell responses in vitro. MG-T-19 partially reversed these alterations, increased CD8⁺ T-cell TNF-α production, and enhanced leukemia-cell apoptosis. In the MLL-AF9 murine AML model, MG-T-19 reduced leukemia burden and prolonged survival.
CONCLUSIONS: Increased monocyte Galectin-9 during early immune reconstitution is associated with subsequent early relapse and CD8⁺ T-cell dysfunction after haplo-HSCT. Further Galectin-9-specific mechanistic studies and prospective clinical validation are warranted to establish its causal relevance and potential utility as an early relapse biomarker.

Keywords:  Acute myeloid leukemia; Early immune reconstitution; Galectin-9; Hematopoietic stem cell transplantation; Monocytes; T cells

DOI:  https://doi.org/10.1186/s40364-026-01010-1
Hemasphere. 2026 Oct;10(10): e70497

A platform of serially transplantable AML PDX models covering subgroups for which no cell lines exist.

Binje Vick, Vindi Jurinovic, Kristina Kuhbandner, Lena Lagally, Lisa Latzko, Chiara Arnreich, Gerulf Hänel, Amelie Muth, Maximilian Schönung, Arnold Kloos, Maja Rothenberg-Thurley, Annika M Dufour, Stephanie Schneider, Lesca M Holdt, Liliana Mura, Fabian Klein, Annette Frank, Dhruv Mehra, Annika Fröhlich, Johannes W Bagnoli, Maya C André, Claudia D Baldus, Martin Carroll, Christine Dierks, Martin Ebinger, Katharina S Götze, Pablo Menéndez, Christian Récher, Ambrine Sahal, Jean-Emmanuel Sarry, Christian Thiede, Talía Velasco-Hernández, Xiaoyan Wei, Jan H Klusmann, Wolfgang Enard, Michael von Bergwelt-Baildon, Wolfgang Hiddemann, Klaus H Metzeler, Philipp A Greif, Michael Heuser, Daniel B Lipka, Marion Subklewe, Sebastian Vosberg, Tobias Herold, Karsten Spiekermann, Irmela Jeremias.

Acute myeloid leukemia (AML) is a highly aggressive malignancy with poor prognosis, underlining the need for suitable model systems to develop novel treatments. To complement the few existing AML cell lines and restricted primografts, we transplanted more than 100 primary AML samples into immunocompromised mice and generated 23 exceptionally robust patient-derived xenograft (*PDX) models of AML that allow virtually unlimited serial transplantation and efficient genetic engineering. These models represent individuals of all age groups and several WHO subgroups. *PDX models substantially outperform AML cell lines in preserving leukemia biology and include AML subgroups for which no cell lines exist, such as cytogenetically normal or IDH1/2-mutant AML or simultaneous NPM1 mutation and FLT3-ITD. Their resilience to freeze-thaw cycles supports broad dissemination across research institutions through sharing via CancerModels.org. Using lentiviruses, we stably expressed luciferase for longitudinal, noninvasive, and sensitive real-time monitoring of leukemia burden and therapeutic response in vivo. This approach enabled rigorously controlled preclinical studies, including phase II-like trials, which demonstrated highly variable treatment responses between different *PDX models, mimicking the heterogeneity in patient cohorts. Long-term treatment, including repeated cytarabine exposure over 1 year, showed a yet undescribed decrease in leukemia's proliferation rate. These insights underscore the platform's distinctive capacity to study treatment dynamics over clinically relevant timeframes. Collectively, our unique resource represents a powerful, robust, and versatile platform with strong potential to accelerate translational AML research for the ultimate benefit of patients.

DOI: https://doi.org/10.1002/hem3.70497
Leukemia. 2026 Oct 09.

Mitochondria transfer via tunneling nanotubes drives macrophage immunosuppression and metabolic reprogramming in pediatric AML.

Alicia Perzolli, Farah Massaoudi, Anita T van Oort, Joost B Koedijk, Elizabeth K Schweighart, Lennart A Kester, Fabienne Adriaanse, Kimberly Smit, Wilbert P Vermeij, Bianca F Goemans, Josef Vormoor, C Michel Zwaan, Olaf Heidenreich.

Although immunotherapy has revolutionized cancer treatment, its benefits in pediatric acute myeloid leukemia (AML) remain limited, partly due to an incomplete understanding of the AML microenvironment. While most studies focus on T cells, innate immune populations such as macrophages are less well explored. In pediatric AML patients, we demonstrate that immunosuppressive macrophages dominate the AML microenvironment and support growth of RUNX1::RUNX1T1 and KMT2A-rearranged leukemic blasts. In co-culture experiments, AML cells reprogrammed naïve and pro-inflammatory macrophages toward an anti-inflammatory state, characterized by suppression of NF-κB and other inflammatory pathways. This phenotypic switch requires direct cell contact and involves tunneling nanotube-mediated transfer of AML mitochondria to macrophages associated with metabolic rewiring toward oxidative phosphorylation. Functionally, these reprogrammed macrophages exhibited impaired phagocytosis, convey chemoresistance and reduced T cell- and bispecific antibody-mediated killing, facilitating immune escape. Our findings reveal a novel mechanism of immune suppression and suggest that targeting AML-macrophage interactions could enhance the efficacy of T cell-based immunotherapies.

DOI: https://doi.org/10.1038/s41375-026-03164-1
Haematologica. 2026 Oct 08.

Neutrophil-derived S100A8/A9 is associated with inflammation that supports Dnmt3a-mutant hematopoiesis.

Jayna J Mistry, Natalie R Fournier, Griffin J Nye, Rongbao Zhao, Amit Verma, Jennifer J Trowbridge.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.301476
Blood Neoplasia. 2026 Nov;3(4): 100281

IMiD/CELMoD resistance in myeloma is associated with changes in lipid metabolism that may be targetable.

Sarah A Bird, Marco P Licciardello, Ananya Sukhtankar, Salomon Morales, Fernando J Sialana, Yitao Xu, Amy Wilson, Harvey Che, Pradeep Ramagiri, Yakinthi Chrisochoidou, Yigen Li, Shannon Martin, Enze Liu, Brian Walker, Jyoti Choudhary, Graham Jackson, Martin Kaiser, Habib Bouguenina, Paul A Clarke, Hector Keun, Charlotte Pawlyn.

Immunomodulatory drugs (IMiDs) are a cornerstone of multiple myeloma treatment, and newer cereblon E3 ligase modulatory drugs (CELMoDs) are in clinical trials. However, a major barrier to improving patient outcomes is the inevitable development of resistance to these agents. To explore the mechanisms underlying IMiD/CELMoD resistance and identify novel targets for treatment, human cell line models of acquired IMiD/CELMoD resistance were generated. A quantitative proteome analysis of these models identified common changes in lipid synthesis proteins, and glucose-labeling experiments confirmed altered lipid flux. Proteomic analysis of paired patient samples at diagnosis and relapse on IMiD suggested similar changes in lipid pathways. A genome-wide CRISPR screen performed in a human multiple myeloma cell line with acquired CELMoD resistance identified dependencies in the lipid pathway genes stearoyl-CoA desaturase and membrane-bound transcription factor peptidase, site 1. This study has led to novel insights into lipid pathway changes in the IMiD/CELMoD-resistant state, which may represent targetable cancer cell vulnerabilities.

DOI: https://doi.org/10.1016/j.bneo.2026.100281
Nat Aging. 2026 Oct 05.

Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.

Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.

Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

DOI: https://doi.org/10.1038/s43587-026-01240-w
Leukemia. 2026 Oct 05.

Recombinant hematopoietic growth factors in acute myeloid leukemia.

Margery Gang, Robert Peter Gale, Roland B Walter.

DOI: https://doi.org/10.1038/s41375-026-03158-z
Leukemia. 2026 Oct 08.

Novel RNA polymerase I and cyclin-dependent kinase combination therapy for the treatment of aggressive acute myeloid leukemia.

Nadine Hein, Perlita Poh, Jason A Powell, Lorena Núñez Villacís, Sarah Sant'Anna Maranhão, Maurits Evers, Jirawas Sornkom, Victoria S Pope, Priscilla Soo, Adria Closa, Jasmina Frawley, Sheren J Al-Obaidi, Cathryn M Gould, Piyush Madhamshettiwar, Kaylene J Simpson, Vijay Bhoopalan, Dani Tutuka, Stuart M Pitson, Luc Furic, Konstantin Panov, Katherine M Hannan, Amee J George, Ross D Hannan, Rita Ferreira.

Despite advances in therapy, specific subtypes of Acute Myeloid Leukemia (AML) remain largely incurable. The small molecule drug CX-5461 exhibits dual target specificity, acting as a first-in-class ribosome biogenesis inhibitor to induce the nucleolar surveillance pathway (NSP), as well as to poison Topoisomerase IIα (TOPIIA) to induce DNA damage. We conducted a phenotypic screen of FDA-approved drugs to identify compounds that synergies with CX-5461 to enhance the therapeutic efficacy of this drug in incurable AML. The pan-CDK inhibitors Dinaciclib and Flavopiridol were identified as efficient combinatorial therapies with CX-5461. Dinaciclib acts synergistically across a genetically divergent panel of human AML cell lines, significantly improves survival in murine AML models, and reduces colony formation in primary human AML samples. Synergy was attributable, at least partially, to combinatorial activation of the NSP. Both agents independently stabilized p53 but produced distinct biological outcome; Dinaciclib driving rapid apoptosis and CX-5461 primarily promoting cell-cycle arrest; which together yielded efficient tumor clearance and delayed onset of therapy resistance. These findings provide strong evidence that a combination treatment strategy that leverages nucleolar stress and cell cycle control to enhance treatment outcomes in AML, paving the way for clinical translation of Pol I-CDK co-targeting therapies.

DOI: https://doi.org/10.1038/s41375-026-03148-1
Small Methods. 2026 Oct 05. e71091

Prediction of Oxidative Stress- and Anticancer Drug-Induced Cellular Senescence Using Holotomography and Interpretable Attention-Based Contrastive Learning.

Avinash Yaganapu, Amarnath Singam, Sai Phani Parsa, Calvinique Lee, Jennifer Zheng, Sunjeet Saha, Jeong Hee Kim, Seungman Park, Mingon Kang.

  Quantitative assessment of the complex morphological and structural changes of cells and organelles during senescence is critical for understanding the level of senescence, which is a key step toward developing anti-aging therapeutics and preventing aging-related diseases. Despite its importance, a robust quantitative method for evaluating cellular senescence is still lacking. Recent advances in holotomography (HT), a label-free imaging technique, address these challenges by enabling high-contrast cell imaging with subcellular specificity, which enables accurate detection and characterization of senescent cells, without the constraints of fluorescence-based imaging. In this study, we introduce an artificial intelligence (AI)-powered Biologically Interpretable Contrastive and Attention-based Network integrated with HT, called BICAN-HT, which leverages high-resolution images to analyze nucleus-cytoplasm interactions for biologically interpretable and quantitative assessment of cellular senescence with enhanced predictive power. We conducted in-depth experiments inducing cellular senescence using three stressors, including hydrogen peroxide (H2O2), doxorubicin (Dox), and palbociclib (Pal), across two different cell lines. BICAN-HT consistently outperformed current state-of-the-art models across multiple stress conditions and cell types, while capturing the morphological features and spatial relationships of cells and organelles within the nucleus and cytoplasm during senescence. BICAN-HT has the potential to transform aging research and accelerate the development of anti-aging interventions.

Keywords:  artificial intelligence; contrastive learning; cross‐attention; holotomography; senescence; stressor

DOI:  https://doi.org/10.1002/smtd.71091