bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–12–28
sixteen papers selected by
William Grey, University of York
  1. Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States.
  2. How to drug a leukemic stem cell: deciphering heterogeneity for better specificity.
  3. A microgel bone marrow model of mesenchymal stem cell paracrine signaling supporting hematopoietic stem cell retention.
  4. Targeting dysregulated epigenetic and transcription factor networks in KMT2A-rearranged AML using iPSC models.
  5. LRG1 Drives AML Progression by Disrupting Myeloid Progenitor Regulation.
  6. Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion.
  7. TAF4B knockdown differentially affects erythroid and natural killer cells but not monocytic differentiation from human cord blood HSPCs.
  8. Protocol for isolation of lipid droplets and mitochondria from acute myeloid leukemia cells for lipidomic analysis.
  9. Flow cytometric detection of leukemic stem cells in Acute Myeloid Leukemia: current status and future directions.
  10. Leukemia-driven expansion of type 3 innate lymphoid cell facilitates a pro-tumoral microenvironment in acute myeloid leukemia.
  11. IFNγ signaling drives resistance to FLT3 inhibition in acute myeloid leukemia.
  12. Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
  13. Multi-scale classification decodes the complexity of the human E3 ligome.
  14. Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy.
  15. Targeting the NLRP3 inflammasome signalling in acute myeloid leukemia: Mechanisms, therapeutics, and future directions.
  16. Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence during collective cell migration.
  1. bioRxiv. 2025 Dec 15. pii: 2025.12.12.694052. [Epub ahead of print]
    Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States.
    Helena Yu, Yoon Joon Kim, Katelyn Chen, Andrea Z Liu, Mary Jean Sunshine, Robert A J Signer.
      Hematopoietic stem cells (HSCs) must preserve protein homeostasis (proteostasis) despite dramatic changes in proliferative and biosynthetic demands during development, yet how proteostasis is regulated across these transitions is poorly understood. Here, we show that fetal and neonatal HSCs operate through distinct, stage-specific proteostasis programs that differ fundamentally from those in adulthood. Using quantitative in vivo assays spanning embryonic through adult stages, we uncover an unanticipated decoupling between protein synthesis and protein quality control during development, revealing that fetal and neonatal HSCs employ specialized mechanisms to safeguard proteome integrity under developmental stress. Developing HSCs experience a distinctive proteostasis landscape characterized by elevated protein synthesis, increased unfolded protein burden, and selective engagement of stress-buffering and protein degradation pathways that are largely dispensable in young adult HSCs. Disruption of these pathways compromises early life HSC function and long-term fitness, establishing proteostasis control as a key regulator of stem cell maturation. These findings define previously unrecognized mechanisms by which HSCs manage the proteome during early life and reveal fundamental principles governing stem cell proteostasis across ontogeny.
    DOI:  https://doi.org/10.64898/2025.12.12.694052
  2. Blood Neoplasia. 2025 Nov;2(4): 100146
    How to drug a leukemic stem cell: deciphering heterogeneity for better specificity.
    Alice Worker, Nicholas Jinks, Peter Woodmancy, Claire Seedhouse, Sophie G Kellaway.
      Blood cancers, such as acute myeloid leukemia (AML), are becoming increasingly common due to an aging population but remain challenging to treat. Relapse is the most important singular cause of treatment failure in AML, and up to half of patients relapse after chemotherapy or bone marrow transplantation. Relapse in AML is primarily due to a population of quiescent leukemic stem cells (LSCs) that shelter in the bone marrow. Chemotherapy hits actively proliferating AML blasts, but LSCs escape and can later re-enter the cell cycle to regenerate the leukemia. LSCs resemble hematopoietic stem cells, but variable and unique differences may allow for LSC-specific treatment. In this review, we summarize the unique biology of LSCs, considering both global and subtype-specific traits. We describe how heterogeneity, both between different AML subtypes and within the LSC compartment, has impaired efforts to find drug targets so far and how this is being resolved with technological advances such as single-cell sequencing. We elucidate which aspects of LSC biology determine possibilities for targeted treatment and the progress so far made toward therapies to prevent or treat relapse.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100146
  3. bioRxiv. 2025 Dec 09. pii: 2025.12.05.692616. [Epub ahead of print]
    A microgel bone marrow model of mesenchymal stem cell paracrine signaling supporting hematopoietic stem cell retention.
    Gunnar B Thompson, Kaila M Kuo, Andrés J García, Brendan A C Harley.
      Hematopoietic stem cells (HSCs) housed within the bone marrow give rise to the full complement of blood and immune cells. Methods to expand HSCs ex vivo have traditionally relied on two-dimensional or liquid culture, but hydrogel approaches have been hypothesized to provide three-dimensional bone marrow-associated biophysical and biomolecular signals that may improve HSC expansion and maintenance ex vivo . Here, we describe a granular biomaterial approach to create a multicellular model of the bone marrow. By seeding HSCs amongst mesenchymal stromal cell (MSC)-laden hydrogel microspheres (microgels), we establish paracrine-mediated interactions between HSCs and hydrogel encapsulated MSCs. We provide support for the importance of microgel encapsulation for the emergence of niche-favorable MSC transcriptional profiles. We identify a common cell culture media that accommodates MSC activity while avoiding the use of serum that typically induces differentiation of HSCs. We observe an MSC-density-dependent increase in maintenance of long-term repopulating HSCs in granular co-culture, and we identify significant depletion of long-term repopulating HSCs when both HSCs and MSCs are interstitially seeded in the granular matrix. Together, these findings establish a granular hydrogel co-culture model to examine the influence of MSC-HSC interactions on maintenance and expansion of HSCs in a defined three-dimensional engineered tissue.
    DOI:  https://doi.org/10.64898/2025.12.05.692616
  4. Blood Neoplasia. 2026 Feb;3(1): 100172
    Targeting dysregulated epigenetic and transcription factor networks in KMT2A-rearranged AML using iPSC models.
    Anna Palau, Jonas Thier, Aonghus Naughton, Andrew Tae-Jun Kwon, David Cabrerizo Granados, Sophia Hofmann, Bogumił Kaczkowski, Xiangfu Zhong, Sören Lehmann, Erik Arner, Vanessa Lundin, Andreas Lennartsson.
      KMT2A chromosomal rearrangements (KMT2A-r) are frequent in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. The KMT2A gene encodes a histone lysine methyltransferase responsible for maintaining active chromatin marks (H3K4me3) at gene promoters and enhancers. KMT2A-r lead to the formation of oncogenic KMT2A fusion proteins with over 70 potential partners, disrupting normal hematopoiesis and driving leukemogenesis. Among these, KMT2A::MLLT3, a fusion of KMT2A and MLLT3, is one of the most prevalent in AML. Disruption of the epigenome is a hallmark of AML, with recurrent abnormalities in epigenetic regulators. These alterations often occur early as disease-initiating events, making epigenetic-targeted therapeutics a promising avenue for treatment. Induced pluripotent stem cells (iPSCs) have emerged as faithful models of human AML pathogenesis, recapitulating the underlying genomic lesions and epigenetic profiles. We investigated transcriptional regulation of hematopoietic development using iPSCs derived from a patient with AML with the KMT2A::MLLT3 rearrangement. Our analysis identified key transcriptional activators and repressors that contribute to the altered regulatory landscape in KMT2A::MLLT3 AML. Further analysis of chromatin immunoprecipitation sequencing data indicated that a significant subset of genes, whose expression was downregulated in AML iPSC-derived hematopoietic stem and progenitor cells (AML-HSPCs), were direct targets of Polycomb Repressive Complex 2 (PRC2). Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in KMT2A-rearranged AML.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100172
  5. Blood Lymphat Cancer. 2025 ;15 235-246
    LRG1 Drives AML Progression by Disrupting Myeloid Progenitor Regulation.
    Rongxia Guo, Peng Wu, Shuxin Yao, Fumei Liu.
       Background: Acute myeloid leukemia (AML) remains clinically challenging due to its molecular heterogeneity and poor outcomes, highlighting the urgent need for novel biomarkers and therapeutic targets.
    Purpose: This study aims to identify and characterize the role of leucine-rich α-2-glycoprotein 1 (LRG1) in AML, evaluating its potential as both a prognostic biomarker and a therapeutic target.
    Methods: We conducted an integrated basic and clinical investigation of LRG1 in AML. Methods included analysis of LRG1 expression in patient samples versus controls and pre- versus post-treatment, assessment of its clinical correlations with mutations and subtypes, and evaluation of its prognostic impact. Functional validation was performed using LRG1 knockdown models to assess effects on colony formation, apoptosis, and differentiation. Single-cell RNA profiling was utilized to identify LRG1-enriched cell populations and explore its role in microenvironmental crosstalk.
    Results: Integrated analysis revealed significantly elevated LRG1 expression in AML patients compared to controls (P<0.001), with levels decreasing post-treatment (P<0.001). High LRG1 expression correlated with FLT3 mutations (P<0.01), M3-M5 AML subtypes (M0&M1&M2 VS M3, P<0.001; M0&M1&M2 VS M4, P<0.01; M0&M1&M2 VS M5, P<0.001; M3 VS M5, P<0.05; M4 VS M5, P<0.05), and worse survival (P<0.01). Functionally, LRG1 knockdown impaired colony formation (P<0.001), increased apoptosis (P<0.001), and disrupted differentiation (P<0.01). Single-cell profiling identified LRG1 enrichment in hematopoietic stem and progenitor cells (HSPCs) and myeloid progenitors, where it facilitated microenvironmental crosstalk via Macrophage Migration Inhibitory Factor (MIF), Galactoside-binding lectin (GALECTIN), and Cyclophilin A (CypA) signals.
    Conclusion: Our findings establish LRG1 as a robust prognostic biomarker and a key functional regulator of AML maintenance through myeloid progenitor dysregulation, presenting it as a promising target for new therapeutic strategies.
    Keywords:  AML; LRG1; hematopoietic dysregulation; microenvironmental crosstalk
    DOI:  https://doi.org/10.2147/BLCTT.S556618
  6. Cell Rep. 2025 Dec 24. pii: S2211-1247(25)01542-6. [Epub ahead of print]45(1): 116770
    Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion.
    Maria Jassinskaja, Daniel Bode, Monika Gonka, Theodoros I Roumeliotis, Alexander J Hogg, Juan A Rubio Lara, Ellie Bennett, Joanna Milek, Samuel Elberfeld, Bart Theeuwes, M S Vijayabaskar, Lilia Cabrera Cosme, James Lok Chi Che, Sandy MacDonald, Sophia Ahmed, Benjamin A Hall, Grace Vasey, Helena Kooi, Miriam Belmonte, Mairi S Shepherd, William J Brackenbury, Iwo Kucinski, Satoshi Yamazaki, Andrew N Holding, Alyssa H Cull, Nicola K Wilson, Berthold Göttgens, Jyoti Choudhary, David G Kent.
      Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), few studies exist at the protein level. We perform a deep, multi-omics characterization (epigenome, transcriptome, and proteome) of HSCs in a mouse model carrying a loss-of-function mutation in Tet2, a driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile TET2-deficient (Tet2-/-) HSCs, revealing previously unrecognized molecular processes that define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of wild-type and Tet2-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as being dysregulated upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
    Keywords:  CP: stem cell research; TET2; biophysics; extracellular matrix; hematopoietic stem cell; multi-omics; physical biology; proteomics; self-renewal; single cell biology
    DOI:  https://doi.org/10.1016/j.celrep.2025.116770
  7. Biochem Biophys Res Commun. 2025 Dec 15. pii: S0006-291X(25)01849-2. [Epub ahead of print]797 153133
    TAF4B knockdown differentially affects erythroid and natural killer cells but not monocytic differentiation from human cord blood HSPCs.
    Saori Nakano, Akira Niwa, Yohko Kitagawa, Megumu K Saito.
      Hematopoietic stem and progenitor cells (HSPCs) rely on coordinated transcriptional programs, yet lineage-specific functions of general transcription machinery components remain unclear. We examined the contribution of TATA-binding protein-associated factor 4B (TAF4B) in human cord blood-derived Lin-CD34+ HSPCs using shRNA-mediated knockdown across colony-forming unit (CFU) assays and directed differentiation. TAF4B knockdown reduced CFU-Mix output, whereas BFU-E and CFU-GM were unchanged. In directed erythroid culture, the proportion of CD71+CD235a+ cells was preserved, but total erythroid cell numbers and HBB transcripts decreased, while HBG and GATA1/KLF1/BCL11A mRNA remained unchanged. In monocytic differentiation, CD14+CD11b+ fractions and counts were not affected. During NK cell differentiation, CD56+ frequency was maintained, but the number and proportion of CD16+ cells declined, accompanied by reduced TBX21 with minimal change in EOMES. These findings indicate lineage- and stage-dependent sensitivity to partial TAF4B perturbation, with unresolved causality and mechanisms requiring orthogonal genetic and chromatin-focused studies.
    Keywords:  CD16; Hematopoiesis; Hemoglobin; NK cell; TAF4B
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153133
  8. STAR Protoc. 2025 Dec 15. pii: S2666-1667(25)00663-X. [Epub ahead of print]6(4): 104257
    Protocol for isolation of lipid droplets and mitochondria from acute myeloid leukemia cells for lipidomic analysis.
    Ran Zhao, Liang Zhang, Shuxin Dong, Kazuharu Kamachi, Saurabh Kumar Gupta, Hiroki Akiyama, Jalen Nguyen, G Lavender Hackman, Michael Andreeff, Alessia Lodi, Jo Ishizawa.
      Lipid droplets (LDs) are dynamic organelles critical for lipid and energy homeostasis. LD dysregulation is implicated in various diseases, including acute myeloid leukemia (AML), which exhibits aberrant lipid metabolism and chemoresistance. Here, we describe an effective protocol for the co-isolation of LDs and mitochondria from lipid-deficient cell types, e.g., AML cells. We detail procedures for the isolation, quality verification, and results from mass spectrometry-based lipidomic analysis. This protocol enables the functional study of organellar lipidomic regulation in AML.
    Keywords:  cancer; cell biology; cell isolation; cell separation/fractionation; mass cytometry
    DOI:  https://doi.org/10.1016/j.xpro.2025.104257
  9. Front Pharmacol. 2025 ;16 1724473
    Flow cytometric detection of leukemic stem cells in Acute Myeloid Leukemia: current status and future directions.
    Mariam M Youssef, Christopher Y Park.
      The assessment of measurable residual disease (MRD) plays a critical role in acute myeloid leukemia (AML) treatment response evaluation and prognosis. However, current AML MRD detection by flow cytometry (FC) is limited in sensitivity due to immunophenotypic variability, similarities to normal hematopoietic stem/progenitor cells, and the lack of stable leukemia-associated immunophenotypes. A significant proportion of AML patients classified as MRD-negative by FC eventually relapse, likely due to the persistence of therapy-resistant leukemic stem cells (LSCs) that are not sensitively detected by routine clinical flow panels. Flow cytometry panels designed to detect LSC antigens, while promising, face challenges like immunophenotypic heterogeneity across AML subtypes, lack of standardized marker panels across laboratories, and limited validation. Here, we summarize the current state of FC-based LSC detection in AML, discussing commonly used markers, immunophenotypic variability, assay setup challenges, and we review recent clinical studies on LSC assessment, outlining their main findings and implications for prognosis and MRD integration. We also consider advances in spectral flow cytometry for improved LSC detection.
    Keywords:  AML-acute myeloid leukemia; LSC-leukemic stem cells; MRD-measurable residual disease; flow cytometry; therapeutic targeting biomarkers
    DOI:  https://doi.org/10.3389/fphar.2025.1724473
  10. Leukemia. 2025 Dec 22.
    Leukemia-driven expansion of type 3 innate lymphoid cell facilitates a pro-tumoral microenvironment in acute myeloid leukemia.
    Thanh Thanh T Dinh, Matthew R Lordo, Amy Y Zhang, Chinmayee Goda, Nikolas Shilo, Ekaterina Altynova, Michael Ruesch, Parker Kronen, Megan Broughton, Erin Jeremy, Victoria L Sellers, Xiaoli Zhang, Karilyn T Larkin, Patrick L Collins, Adrienne M Dorrance, Aharon G Freud, Christopher C Oakes, Bethany L Mundy-Bosse.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is incompletely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity through cytokine secretion. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. The transcription factor, aryl hydrocarbon receptor (AHR) is required for ILC3 development and function, and AML blasts have been shown to secrete AHR ligands. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation in ILC precursors. ILC3s developed in leukemic settings had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by ILC3-derived TNFα and GM-CSF. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo and human ILC3 frequency was associated with adverse risk stratification in AML patients. These data support a model in which AML promotes ILC3 expansion and function via an AHR-dependent mechanism to aid AML growth and survival.
    DOI:  https://doi.org/10.1038/s41375-025-02829-7
  11. iScience. 2025 Dec 19. 28(12): 114079
    IFNγ signaling drives resistance to FLT3 inhibition in acute myeloid leukemia.
    Abraheem Khouqeer, Justin Cartailler, Christina Kim, Kirsten M Dickerson, Chad R Potts, Anna E Gilbert, Robert S Welner, P Brent Ferrell.
      Resistance to targeted therapies remains a major challenge in acute myeloid leukemia (AML). In FLT3-internal tandem duplication (FLT3-ITD) AML, FLT3 inhibitors such as quizartinib improve outcomes, but resistance limits long-term efficacy. While genetic resistance mechanisms are well characterized, the role of the bone marrow microenvironment remains unclear. We investigated how a pro-inflammatory microenvironment influences FLT3 inhibitor resistance and identified IFNγ as a key driver. IFNγ signaling activates STAT1, which in turn upregulates AXL, allowing leukemia cells to survive despite FLT3 inhibition. Knockdown, genomic degron tagging, and overexpression cell models confirmed STAT1 and AXL roles as mediators of resistance. Finally, analysis of IFNγ signaling and resistance in patient-derived AML blasts revealed variable sensitivity, suggesting the presence of additional compensatory mechanisms. These findings reveal IFNγ signaling as a mechanism of resistance, highlighting a potential therapeutic vulnerability in FLT3-mutated AML.
    Keywords:  cancer; cell biology; immunology; microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2025.114079
  12. bioRxiv. 2025 Dec 12. pii: 2025.12.09.693285. [Epub ahead of print]
    Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
    Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.
      Cells dynamically regulate chromatin in response to nutrient flux which promotes the transcriptional changes necessary for adaptation. The mechanistic target of rapamycin complex 1 (mTORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin stability feeds back to mTORC1 activation and stress adaption remains unknown. We previously identified histone H3 at lysine 37 (H3K37) as essential for the response to mTORC1 stress such that mutation of H3K37 to alanine (H3K37A) causes cell death upon mTORC1 inhibition. Herein, we show that H3K37-dependent chromatin stability prevents proteasome-mediated histone degradation, restricts mTORC1 signaling, and safeguards mitochondrial homeostasis during mTORC1 stress. Genetic interaction analyses reveal that H3K37A combined with mutants that destabilize chromatin, including loss of the Set2 H3K36 methyltransferase, Rpd3S histone deacetylase, or multiple histone deposition pathways, causes synthetic lethality when mTORC1 is inhibited. Transcriptome analysis indicates that H3K37A misregulates the mitochondrial transcriptome during mTORC1 stress, which increases mitochondrial reactive oxygen species (ROS) and triggers lethal mitochondrial retrograde signaling. Inactivation of retrograde signaling, or ROS neutralization, rescues viability of H3K37A and chromatin stability mutants during mTORC1 stress. These findings establish chromatin stability as a key safeguard that restrains mTORC1 activity and prevents toxic mitochondrial stress during metabolic adaptation.
    DOI:  https://doi.org/10.64898/2025.12.09.693285
  13. Nat Commun. 2025 Dec 25. 16(1): 11382
    Multi-scale classification decodes the complexity of the human E3 ligome.
    Arghya Dutta, Alberto Cristiani, Siddhanta V Nikte, Jonathan Eisert, Yves Matthess, Borna Markusic, Cosmin Tudose, Chiara Becht, Varun Jayeshkumar Shah, Thorsten Mosler, Koraljka Husnjak, Ivan Dikic, Manuel Kaulich, Ramachandra M Bhaskara.
      E3 ubiquitin ligases are vital enzymes that define the ubiquitin code in cells. Beyond promoting protein degradation to maintain cellular health, they also mediate non-degradative processes like DNA repair, signaling, and immunity. Despite their therapeutic potential, a comprehensive framework for understanding the relationships among diverse E3 ligases is lacking. Here, we classify the "human E3 ligome"-an extensive set of catalytic human E3s-by integrating multi-layered data, including protein sequences, domain architectures, 3D structures, functions, and expression patterns. Our classification is based on a metric-learning paradigm and uses a weakly supervised hierarchical framework to capture authentic relationships across E3 families and subfamilies. It extends the categorization of E3s into RING, HECT, and RBR classes, including non-canonical mechanisms, successfully explains their functional segregation, distinguishes between multi-subunit complexes and standalone enzymes, and maps E3s to substrates and potential drug interactions. Our analysis provides a global view of E3 biology, opening strategies for drugging E3-substrate networks, including drug repurposing and designing specific E3 handles.
    DOI:  https://doi.org/10.1038/s41467-025-67450-9
  14. bioRxiv. 2025 Dec 18. pii: 2025.12.16.693978. [Epub ahead of print]
    Romaciclib, a CDK8/CDK19 inhibitor, can overcome venetoclax resistance through a combinatorial strategy.
    Urszula Pakulska, Marta Obacz, Jerzy Woźnicki, Katarzyna Wiklik, Samarpana Chakraborty, Marta Micek, Vakul Mohanty, Diego Coelho, Elżbieta Adamczyk, Aniela Gołas, Adrianna Moszyńska, Hui Zhang, Magdalena Cybulska-Lubak, Ewelina Kaniuga, Zuzanna Sadowska-Markiewicz, Marina Konopleva, Michał Mikula, Przemysław Juszczyński, Aditi Shastri, Natalia Baran, Tomasz Rzymski, Milena Mazan.
      The combination of venetoclax (VEN) and hypomethylating agents (HMA) is the standard of care in acute myeloid leukemia (AML) for elderly patients unfit for intensive chemotherapy. Despite its clinical success, most patients eventually relapse, creating an urgent need for effective therapeutic alternatives. In this study, we aimed to evaluate the potential of romaciclib, a first-in-class CDK8/CDK19 inhibitor, in combination with VEN to overcome stroma-mediated and primary/acquired VEN-resistance. We assessed the efficacy of RVU120+VEN combination in both sensitive and resistant AML cell lines and primary patient-derived models. Our finding demonstrated that romaciclib synergizes with VEN in AML cell lines and in 8 out of 11 patient-derived cell samples. The proteomic and functional studies demonstrated that combination induced apoptosis through caspase-dependent cleavage of MCL-1. In vivo studies confirmed the efficacy of RVU120+VEN, showing eradication of leukemic cells and bone marrow recovery. Importantly, the combination effectively overcame both stroma-mediated and transcriptionally dependent VEN-resistance. Mechanistic studies, focusing on transcriptomic analyses, identified key resistance-associated pathways, including IL6/JAK/STAT3, TGF-β, PI3K/AKT/MTOR, and inflammatory signaling, being suppressed by combination treatment. Furthermore, an in vivo study using a VEN-resistant patient-derived xenograft (PDX) model confirmed the efficacy of the combination, demonstrating a significant reduction in leukemia burden and a decreased proportion of leukemia initiating cells (LIC) following treatment. These findings prove the highly synergistic mechanism of action of RVU120+VEN combination and the potential to overcome primary/acquired VEN resistance in relapse/refractory AML disease. Altogether, the presented results support ongoing clinical studies evaluating romaciclib and VEN in VEN/HMA-refractory patients ( NCT06191263 ) and provide a basis for future exploration as a frontline therapy in VEN-naïve patients.
    DOI:  https://doi.org/10.64898/2025.12.16.693978
  15. Biochim Biophys Acta Mol Basis Dis. 2025 Dec 21. pii: S0925-4439(25)00493-4. [Epub ahead of print] 168143
    Targeting the NLRP3 inflammasome signalling in acute myeloid leukemia: Mechanisms, therapeutics, and future directions.
    Sally H Fayad, Alaa Mohamed Salah, Ayad A Jaffa, Nadine Darwiche.
      Acute myeloid leukemia (AML) is one of the most frequent hematological malignancies. It is a complex and aggressive disease of undifferentiated hematopoietic progenitor cells, with high rates of relapse and drug resistance, posing significant clinical challenges. Emerging evidence underscores the critical role of inflammation in AML progression, with inflammasomes-key regulators of the inflammatory response-emerging as pivotal players in disease pathogenesis. Among these, the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome has gained particular attention due to its involvement in promoting leukemogenesis and chemoresistance. While inflammasomes have been previously studied in various cancer types, no comprehensive review to date has specifically addressed the role of the NLRP3 inflammasome in AML and its potential targeted therapy. Focusing on the NLRP3 inflammasome, we explore its contribution to AML pathogenesis and its therapeutic potential. We highlight preclinical natural and synthetic compounds, alongside clinical-stage and clinically approved drugs that target the NLRP3 inflammasome signalling pathway and components. We address the challenges and limitations of these promising compounds and drugs, while highlighting recent advancements such as the synthesis of novel and derivatives designed to improve their efficacy. Finally, we discuss future research directions aimed at deepening our understanding of the NLRP3 inflammasome and identifying novel and improved therapeutic outcomes against AML.
    Keywords:  Acute myeloid leukemia (AML); Cell signalling; Inflammasome; Inflammation; NLRP3; Targeted therapy
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168143
  16. Nat Commun. 2025 Dec 21.
    Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence during collective cell migration.
    Rituraj Marwaha, Diya Manoj, Simran Rawal, Purnati Khuntia, Sanak Banerjee, Praver Gupta, Basil Thurakkal, Manish Jaiswal, Tamal Das.
      Collective cell migration during embryonic development, wound healing, and cancer metastasis requires the emergence of leader cells at the migration front. Despite their physiological relevance, the full mechanisms underlying the emergence of leader cells remain elusive. Here we report that leader cells display a peripheral accumulation of lysosomes in diverse model systems for wound healing, including cultured epithelial monolayer, mouse embryonic skin, and Drosophila embryos. This accumulation involves cellular contractile forces driving lysosomal transport along microtubules towards the leading edge. Indeed, we control leader cell emergence by manipulating lysosomal movement on microtubules. We further find that peripheral lysosomes associate with Rac1 molecules at the leading periphery, regulating local Rac1-activity, triggering actin polymerization and promoting lamellipodium formation. Taken together, we demonstrate that beyond their catabolic role, lysosomes act as an intracellular platform that links mechanical and biochemical signals to control the emergence of leader cells.
    DOI:  https://doi.org/10.1038/s41467-025-67645-0
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