bims-scepro 2025-08-17 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–08–17
twenty-two papers selected by
William Grey, University of York

Andrographolide promotes the ex vivo expansion of CD34+ hematopoietic stem cells derived from human umbilical cord blood.
Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.
Diet-induced obesity induces oxidative stress and enhances H3K4me3 levels, driving nonresolving inflammation and myelopoiesis in hematopoietic stem and progenitor cells.
Enhanced Hematopoietic Stem Cell Self-Renewal and Engraftment Through Human Lung Exosomal Communication.
The complosome - a key regulator of hematopoietic stem cells and innate immune responses.
Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.
Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation.
GCK inhibition enhances iberdomide antimyeloma effects by promoting IKZF1 degradation via a CRBN-independent mechanism.
Protein Turnover Dynamics Analysis With Subcellular Spatial Resolution.
Inflammatory signaling in the pathogenesis of acute myeloid leukemia.
Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.
Distinct stromal cell populations define the B-cell acute lymphoblastic leukemia microenvironment.
NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation.
Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.
Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.
Principles of cotranslational mitochondrial protein import.
PRMT1-mediated metabolic reprogramming promotes leukemogenesis.
Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML.
A Moments-Based Analytical Approach for Cell Size Homeostasis.
Complementary cytoskeletal feedback loops control signal transduction excitability and cell polarity.
HDAC Inhibition Protects RPE Cells from Oxidative Stress via Enhanced Mitochondrial Fusion, Cytoskeletal Repair, and Nrf-2 Activation.

Sci Rep. 2025 Aug 12. 15(1): 29477

Andrographolide promotes the ex vivo expansion of CD34+ hematopoietic stem cells derived from human umbilical cord blood.

Nareerat Sutjarit, Laongthip Ruknarong, Chamnan Tanprasertkul, Kanit Bhukhai, Hay Man Saung Hnin Soe, Pakpoom Kheolamai, Sirikul Manochantr, Chairat Tantrawatpan, Duangrat Tantikanlayaporn.

  Umbilical cord blood (UCB) units are an alternative source of human hematopoietic stem cells (HSCs) for allogeneic stem cell transplants. A large quantity of HSCs is needed but the low number of accessible cells from UCB has been a significant limitation. Improving the ex vivo growth of HSCs while preserving their functioning is required. Here, we report that andrographolide (AP) enhanced the expansion of human UCB-derived HSCs (HSPCs) and pro-moted primitive HSCs (CD34+CD38-CD90+). AP also improved HSC functionality, evidenced by increased growth of colony-forming units and multilineage differentiation. AP upregulated genes involved in the Wnt/β-catenin and Notch signaling pathways. AP also modulated signaling pathways involved in HSC self-renewal, proliferation, survival, and differentiation, demonstrated by Nanostring analysis. The results of this study suggest that andrographolide enhances ex vivo UCB-HSC expansion while maintaining functionality and has potential for treatment of hematological diseases.

Keywords:  Andrographolide; Ex vivo expansion; Hematologic disorders; Hematopoietic stem cell transplantation; Hematopoietic stem cells (HSCs); Umbilical cord blood (UCB)

DOI:  https://doi.org/10.1038/s41598-025-15647-9
bioRxiv. 2025 Jul 15. pii: 2025.07.11.663968. [Epub ahead of print]

Exploiting an Epigenetic Resistance Mechanism to PI3 Kinase Inhibition in Leukemic Stem Cells.

Shira G Glushakow-Smith, Imit Kaur, Simone Sidoli, Shayda Hemmati, Ellen Angeles, Taneisha Sinclair, Samarpana Chakraborty, Aaliyah Battle, Kristina Ames, Swathi-Rao Narayanagari, Rotila Hyka, Mark Soto, Melissa Tracy, Jayaram Vankudoth, Seiya Kitamura, Linde Miles, Ulrich Steidl, Aditi Shastri, Amit Verma, Kira Gritsman.

Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute myeloid leukemia (AML) patients, and inability to target leukemic stem cells (LSCs) can lead to relapse. To overcome these challenges, we tested whether LSCs have dependencies on PI3 kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the P110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as a resistance mechanism in response to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregulation of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this resistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully overcomes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.

DOI: https://doi.org/10.1101/2025.07.11.663968
J Immunol. 2025 Aug 07. pii: vkaf156. [Epub ahead of print]

Diet-induced obesity induces oxidative stress and enhances H3K4me3 levels, driving nonresolving inflammation and myelopoiesis in hematopoietic stem and progenitor cells.

Kentaro Takahashi, Julia Drolet, Jinghua Liu, Jasmine R Jackson, Muthusamy Thiruppathi, Milie Fang, Jack Rogers, Ian Davis, Giamila Fantuzzi, Elizaveta V Benevolenskaya, Timothy J Koh, Norifumi Urao.

  Diet-induced obesity leads to dysregulated myelopoiesis and nonresolving inflammation. Such dysregulation could involve epigenetic reprogramming, which can induce long-term changes in hematopoietic stem and progenitor cells (HSPCs). However, whether and how obesity-dysregulated HSPCs impact myelopoiesis in response to tissue injury are not fully understood. Here, we tested the hypothesis that obesity induces oxidative stress and histone H3 lysine-4 trimethylation (H3K4me3) in HSPCs, programming enhanced myelopoiesis and persistent inflammation, leading to impaired tissue recovery. Transfer of bone marrow HSPCs from high-fat diet-induced obese mice (HFD-HSPCs) to lean recipients was sufficient to drive nonresolving myelopoiesis and impaired tissue recovery from hindlimb ischemia. HFD-HSPCs exhibited increased oxidative stress that drives elevated H3K4me3 and reduced KDM5 demethylase activity. CUT&Tag (cleavage under targets and tagmentation) analysis revealed H3K4me3 enrichment at cell cycling regulating E2F targets during myeloid differentiation and Tlr4 gene promoter in HFD-HSPCs. Such enrichment is associated with increased TLR4-driven myelopoiesis in vitro, increased inflammatory myelopoiesis during hindlimb ischemia, and myeloid bias after serial transplantations in lean recipients. Knockout of KDM5A, an H3K4me3 demethylase and negative regulator of E2F activity, increased H3K4me3 in HSPCs, enhanced TLR4-driven myelopoiesis in vitro, and increased myelopoiesis in vivo. Furthermore, cyclosporine A treatment in HSPCs ex vivo reduced oxidative stress, normalized H3K4me3 levels, and mitigated enhanced myelopoiesis in HSPCs in HFD mice. Our findings suggest that oxidative stress by diet-induced obesity enhances H3K4me3 levels and increases myelopoiesis in HSPCs, leading to persistent inflammation and impaired recovery from hindlimb ischemia.

Keywords:  epigenetics; hematopoietic stem; myelopoiesis; obesity; oxidative stress; progenitor cells

DOI:  https://doi.org/10.1093/jimmun/vkaf156
Mol Ther. 2025 Aug 11. pii: S1525-0016(25)00649-5. [Epub ahead of print]

Enhanced Hematopoietic Stem Cell Self-Renewal and Engraftment Through Human Lung Exosomal Communication.

Sanam Rezaei Benam, Xuepeng Wang, Samaneh Maleknia, Reuben Kapur, Reza Shahbazi.

Hematopoietic stem cells are essential for sustaining the hematopoietic system throughout an individual's life. Within the HSC hierarchy, long-term hematopoietic stem cells are at the apex, maintaining the system by their unique capacity for self-renewal and differentiation into all blood cell lineages. Traditionally, it was believed that long-term hematopoietic stem cell homeostasis is solely regulated within the bone marrow niche. However, our innovative single cell exosomal tracking analysis and in vivo transplantation studies revealed that lung cells play a significant role in this regulation through exosomal communication. Our in vivo primary and secondary engraftment studies demonstrate that exosomes derived from human primary small airway epithelial cells significantly enhance hematopoietic stem cell engraftment. We developed a single-cell exosome tracking pipeline to track these exosomes and elucidated their effects on target cell populations. By integrating single-cell RNA sequencing, exosomal miRNA profiling, and proteomics, we have identified specific genes, miRNAs, and proteins that regulate hematopoietic stem cell function, providing a comprehensive understanding of the molecular mechanisms involved in homeostasis. This insight suggests potential utility in modulating HSC function under experimental conditions, especially in conditions associated with low stem cell fitness including sickle cell disease and bone marrow failure.

DOI: https://doi.org/10.1016/j.ymthe.2025.08.020
Leukemia. 2025 Aug 13.

The complosome - a key regulator of hematopoietic stem cells and innate immune responses.

Henning Ulrich.

DOI: https://doi.org/10.1038/s41375-025-02728-x
bioRxiv. 2025 Jul 16. pii: 2025.07.16.664824. [Epub ahead of print]

Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.

Peng Lyu, Gaurav Agarwal, Chun-Jie Guo, Tianyi Ye, Chen Weng, Mateusz Antoszewski, Samantha Joubran, Alexis Caulier, Michael Poeschla, Vijay G Sankaran.

The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9 , which we have named HOTSCRAMBL . The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9 , in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA -dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.

DOI: https://doi.org/10.1101/2025.07.16.664824
Cell Death Dis. 2025 Aug 12. 16(1): 611

Cathepsin D promotes acute myeloid leukemia progression through stabilization of the anti-apoptotic proteins.

Huimin Jiang, Yongjian Wang, Churan Wang, Lu Yang, Shujuan Wang, Feng Wang, Situ Xue, Zhuan Zhang, Haigen Fu, Ting Dong, Jian Yuan, Zhuorong Li, Ke Li.

Cathepsin D (CTSD) is a lysosomal aspartic protease that plays vital roles in regulating the properties of solid tumors, including proliferation, apoptosis, migration, metastasis, and angiogenesis. However, the function of CTSD in haematological malignancies remains largely elusive. Here we show that CTSD is highly expressed in acute myeloid leukemia (AML) and that high CTSD expression is associated with unfavourable prognosis. Knockdown of CTSD in AML cells inhibits cell proliferation and anti-apoptotic activity. Mechanistically, CTSD decreased the expression of the E3 ubiquitin ligase TRIM21, which mediates the ubiquitination and degradation of anti-apoptotic proteins BCL2, BCL-XL, and MCL1. Inhibition of CTSD expression via genetics or the small-molecule inhibitor N-8 decreases the protein levels of BCL2, BCL-XL, and MCL1 through accelerating their degradation. N-8 shows significant efficacy in eradicating AML in both venetoclax-sensitive and -resistant models. Collectively, our study reveals the role of CTSD in leukemia progression and highlights targeting CTSD as a potential therapeutic strategy in AML.

DOI: https://doi.org/10.1038/s41419-025-07949-7
Cell Death Dis. 2025 Aug 15. 16(1): 619

Lysine-specific demethylase 1 regulates hematopoietic stem cell expansion and myeloid cell differentiation.

Hans Felix Staehle, Christoph Koellerer, Anne Marie Staehle, Jana Schulze, Philipp Eble, Anja Müller, Franziska Zell, Judith M Müller, Florian Perner, Aya Attia, Jan-Philipp Mallm, Olga Pozdnyakova, Karsten Rippe, Benedikt Brors, Lars Feuerbach, Charles D Imbusch, Eric Metzger, Roland Schüle, Heike L Pahl, Jonas S Jutzi.

The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In the absence of the LSD1 protein, GFI1 DNA binding is diminished, and myeloid cell differentiation arrests at an immature, myelomonocytic-like cell stage, which overexpresses Prtn3. We provide functional data implicating Prtn3 as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.

DOI: https://doi.org/10.1038/s41419-025-07951-z
Blood Neoplasia. 2025 Aug;2(3): 100130

GCK inhibition enhances iberdomide antimyeloma effects by promoting IKZF1 degradation via a CRBN-independent mechanism.

Shirong Li, Josefine Krüger, Guifen Liu, Huihui Ma, Michael S Hughes, Rajshekhar Chakraborty, Divaya Bhutani, Markus Y Mapara, Christophe Marcireau, Suzanne Lentzsch, Jing Fu.

Our recent study identifies germinal center kinase (GCK) as a novel therapeutic target in RAS-mutated multiple myeloma (MM). Inhibiting GCK downregulates critical transcriptional factors, notably IKZF1/3, BCL-6, and c-MYC proteins, leading to MM cell growth inhibition and cell death. Distinct from immunomodulatory drug (IMiD)-induced IKZF1/3 degradation, GCK inhibition triggers IKZF1/3 proteolysis through a cereblon (CRBN) E3 ligase-independent mechanism. Here, we demonstrated that GCK inhibition overcomes IMiD resistance in MM. An isogenic subline of MM.1S cells with acquired lenalidomide resistance remains sensitive to GCK inhibition-induced IKZF1/3 downregulation and cell growth inhibition. Consistently, the CRBN-resistant IKZF1 Q146H mutant maintains sensitivity to GCK inhibitor-induced degradation, similar to the IKZF1 wild-type protein, suggesting a CRBN-independent protein degradation. In accordance with the distinct IKZF1/3 degradation mechanisms, GCK silencing enhances iberdomide-induced IKZF1/3 and c-MYC downregulation and MM growth inhibition. More importantly, the combination of a GCK inhibitor with iberdomide exhibited synergistic anti-MM effects in a panel of MM cell lines and primary plasma cells. The synergistic effects were confirmed in an MM xenograft mouse model, in which combining GCK silencing and iberdomide resulted in significantly enhanced tumor inhibition and prolonged mice survival compared to single treatments. These findings underscore GCK as a promising therapeutic target for bypassing IMiD resistance in MM. Combining GCK inhibition with iberdomide could provide a novel strategy to manage relapsed or refractory patients with multidrug resistance, especially after the exhaustion of immunotherapy.

DOI: https://doi.org/10.1016/j.bneo.2025.100130
Bio Protoc. 2025 Aug 05. 15(15): e5409

Protein Turnover Dynamics Analysis With Subcellular Spatial Resolution.

Lorena Alamillo, Alexander Black, Maggie P Y Lam, Edward Lau.

  Protein synthesis and degradation (i.e., turnover) forms an important part of protein homeostasis and has been implicated in many age-associated diseases. Different cellular locations, such as organelles and membraneless compartments, often contain individual protein quality control and degradation machineries. Conventional methods to assess protein turnover across subcellular compartments require targeted genetic manipulation or isolation of specific organelles. Here we describe a protocol for simultaneous proteome localization and turnover (SPLAT) analysis, which combines protein turnover measurements with unbiased subcellular spatial proteomics to measure compartment-specific protein turnover rates on a proteome-wide scale. This protocol utilizes dynamic stable isotope labeling of amino acids in cell culture (dynamic SILAC) to resolve the temporal information of protein turnover and multi-step differential ultracentrifugation to assign proteins to multiple subcellular localizations. We further incorporate 2D liquid chromatography fractionation to greatly increase analytical depth while multiplexing with tandem mass tags (TMT) to reduce acquisition time 10-fold. This protocol resolves the spatial and temporal distributions of proteins and can also reveal temporally distinct spatial localizations within a protein pool. Key features • Captures protein turnover rates and subcellular localization of proteins. • Hyperplexing of dynamic SILAC and TMT LOPIT-DC in MS1 and MS2 level data. • Sample collection and processing can be completed within 1 week. • Allows comparison of organellar proteome turnover rates.

Keywords:  Mass spectrometry; Proteomics; Spatial proteomics; Subcellular localization; Temporal proteomics; Turnover

DOI:  https://doi.org/10.21769/BioProtoc.5409
Hemasphere. 2025 Aug;9(8): e70188

Inflammatory signaling in the pathogenesis of acute myeloid leukemia.

Artemis Margrith Baumann, Jana Maria Ellegast.

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem and progenitor cells and the most common malignant myeloid disorder in adults. Extensive research has elucidated the broad spectrum of biological mechanisms contributing to the development of AML and specifically characterized a variety of genetic alterations initiating and defining the disease. However, the role of inflammation in the pathogenesis of AML remains relatively unexplored; indeed, studies on the contribution of inflammatory signaling to disease initiation in myeloid malignancies have only recently gained attention, marking an emerging area of research. AML has the highest incidence in the elderly, where inflammation plays an even greater role. A granular understanding of inflammatory processes driving leukemogenesis thus promises to guide therapeutic strategies for a patient population where outcomes remain dismal. This review offers a comprehensive synthesis of the current knowledge on the role of inflammatory signaling in AML pathogenesis. It discusses the role of inflammation from premalignant states through malignant transformation, dissecting phenotypic, correlative studies from mechanistic evidence. We thereby highlight questions requiring further research to exploit the translational potential of therapies targeting inflammatory signaling and to address challenges with current immune-modulating treatments. A particular focus is placed on assessing the role of inflammation in the interplay with genetic events as established factors in disease initiation and progression to clarify the current understanding of inflammatory signaling in AML pathogenesis.

DOI: https://doi.org/10.1002/hem3.70188
Cancer Discov. 2025 Aug 12.

Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.

Pu Zhang, Zhendong Cao, Xiangyu Pan, Yuqiao Liu, Cynthia Castro, Won Jun Kim, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Sanam Shahid, Jasmine Um, Erin Burns, Bingyi Chen, Winson Cai, Juliana Ortiz-Pacheco, Zhuoning Li, Mara Monetti, Christopher R Vakoc, Anthony F Daniyan, Omar Abdel-Wahab, Junwei Shi.

GAPs (GTPase-activating proteins) and GEFs (guanine nucleotide exchange factors) play key roles in cancer development, but their large number and potential redundancy have limited systematic evaluation. Here we perform unbiased genetic screens to identify GAPs and GEFs with cancer- and lineage-specific requirements, as well as dual perturbation screens to dissect functionally relevant interactors of GAPs and GEFs. Application to primary acute myeloid leukemia (AML) patient specimens uncovers the GAP ARHGAP45 as a targetable dependency shared across cancers of hematopoietic origin while being dispensable in normal hematopoiesis. We demonstrate that targeting ARHGAP45-expressing cells can be achieved through TCR-CAR T cells directed at an ARHGAP45-encoded minor histocompatibility antigen and that pharmacologic targeting of GAPs required upon ARHGAP45 depletion augments ARHGAP45-directed cell therapies. These studies provide a resource for probing oncogenic and druggable regulators of GTPases and strategies to target a GAP that represents a shared dependency across blood cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0299
Leukemia. 2025 Aug 15.

Distinct stromal cell populations define the B-cell acute lymphoblastic leukemia microenvironment.

Mauricio N Ferrao Blanco, Bexultan Kazybay, Mirjam Belderbos, Olaf Heidenreich, Hermann Josef Vormoor.

The bone marrow microenvironment plays a critical role in B-cell acute lymphoblastic leukemia (B-ALL) progression, yet its cellular heterogeneity remains poorly understood. Using single-cell RNA sequencing on patient-derived bone marrow aspirates from pediatric B-ALL patients, we identified two distinct mesenchymal stromal cell (MSC) populations: early mesenchymal progenitors and adipogenic progenitors. Spatial transcriptomic analysis further revealed the localization of these cell types and identified a third stromal population, osteogenic-lineage cells, exclusively present in the bone biopsy. Functional ex vivo assays using sorted stromal populations derived from B-ALL patient bone marrow aspirates demonstrated that both early mesenchymal and adipogenic progenitors secrete key niche-supportive factors, including CXCL12 and Osteopontin, and support leukemic cell survival and chemoresistance. Transcriptomic profiling revealed that B-ALL cells interact differently with stromal subtypes. Notably, adipogenic progenitors, but not early mesenchymal progenitors, provide support to leukemic cells through interleukin-7 and VCAM1 signaling. Stromal cells from B-ALL patients exhibited an enhanced adipogenic differentiation capacity compared to healthy controls. Moreover, co-culture experiments showed that B-ALL cells induce adipogenic differentiation in healthy MSCs through a cell contact-dependent mechanism. Adipogenic progenitors were also enriched in relapse samples, implicating them in disease progression. These findings highlight the complexity of the B-ALL microenvironment and identify different specialized stromal niches with which the leukemic cells can engage.

DOI: https://doi.org/10.1038/s41375-025-02734-z
Blood Neoplasia. 2025 Aug;2(3): 100119

NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies with TP53 inactivation.

Madhavi D Senagolage, Hunter Z Blaylock, Saira Khan, Sarah J Skuli, Martin P Carroll, Megan E McNerney.

Monosomy 7 (-7) and deletions of chromosome arm 7q (del(7q)) are prevalent high-risk cytogenetic abnormalities that often co-occur with del(17p) (harboring TP53). To identify novel targeted therapies based on specific vulnerabilities in high-risk myeloid malignancies, we investigated druggable, chromosome 7-encoded essential genes that are monoallelically deleted in the context of -7/del(7q), that is, collateral lethal genes. By mining genome-wide CRISPR-Cas9 screen data sets, we identified nicotinamide phosphoribosyltransferase (NAMPT) on 7q22.3 as a specific susceptibility in 81.5% of -7/del(7q) malignancies. Human acute myeloid leukemia (AML) cell lines with partial loss of NAMPT and primary samples from patients with -7 AML demonstrated heightened sensitivity to the NAMPT inhibitor KPT-9274 compared to control samples. Notably, NAMPT inhibitors were equally effective in NAMPT-deficient samples with TP53 loss. Furthermore, combining NAMPT and poly (ADP-ribose) polymerase (PARP) inhibitors, which augment DNA damage, resulted in synergistic therapeutic effects in NAMPT-deficient AML cells. These findings indicate that NAMPT heterozygosity is a therapeutic vulnerability in high-risk myeloid malignancies with -7/del(7q) and recommend NAMPT levels as a biomarker for NAMPT inhibitor sensitivity. This study also establishes a data-driven framework for identifying collateral lethal genes in cancers with recurrent chromosomal deletions.

DOI: https://doi.org/10.1016/j.bneo.2025.100119
Blood. 2025 Aug 14. pii: blood.2025028985. [Epub ahead of print]

Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia.

Lindsey E Montefiori, Ilaria Iacobucci, Qingsong Gao, Jamila Moore, William C Wright, Huimei Wei, Pradyumna Baviskar, Surbhi Sona, Hongjian Jin, Amit Budhraja, Josi Lott, Qi Zhang Tatarata, Zhongshan Cheng, Tanya M Khan, Emily A Backhaus, Melissa D Johnson, Cyrus M Mehr, Burgess B Freeman, Laura J Janke, Torsten Haferlach, Paul Geeleher, Paul E Mead, Marina Y Konopleva, Joseph T Opferman, Charles G Mullighan.

Aberrant activation of BCL11B ("BCL11B-a") defines a subtype of lineage ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and FLT3 inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single agent therapies, the combination of venetoclax plus gilteritinib (VenGilt) was highly effective in all models evaluated. BH3 profiling suggested that resistance to venetoclax monotherapy was due to the tumor-intrinsic dependence on additional BCL-2 family proteins prior to drug treatment. Longitudinal single cell RNA-seq analysis identified mitochondrial pathways and a pro-lymphoid gene expression signature as potential drivers of rare cell survival on VenGilt therapy. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.

DOI: https://doi.org/10.1182/blood.2025028985
Blood Adv. 2025 Aug 12. pii: bloodadvances.2025015806. [Epub ahead of print]

Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.

Jingyi Zhang, Zhenwei Zhang, Jinghua Liu, Shenglin Luan, Jiqiang Qu, Zi Wu, Yafei Kuang, Ping Gong, Yu Bao, Yuetong Wang, Xiaojing Yan, Samuel Waxman, Linxiang Zhao, Yongkui Jing.

The Bcl-2 inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in elderly patients with acute myeloid leukemia (AML). However, its clinical efficacy is frequently constrained by the emergence of drug resistance, which involves the overexpression or induction of Mcl-1 and Bcl-xL proteins. To address this challenge, we developed a novel strategy to enhance venetoclax activity and overcome resistance by producing NOXA through the conjugation of dihydroartemisinin (DHA) to venetoclax using a chemical synthesis approach. The resulting conjugate, A1, retains potent Bcl-2 inhibitory activity and significantly enhances NOXA production by promoting interactions between the DHA-derived endoperoxide bridge and heme. Mechanistically, A1 effectively overcomes resistance caused by Mcl-1 and Bcl-xL protein through NOXA-mediated Mcl-1 and cyclin D1 protein degradation, respectively. Optimization of the linker design of A1 yielded PEG-linked conjugates with increased in vivo efficacy. This study introduces a new generation of venetoclax-based compounds with dual functionality: enhanced NOXA production and robust degradation of anti-apoptotic and cell-cycle-regulating proteins. Furthermore, we uncover a promising therapeutic strategy to overcome drug resistance in venetoclax-based AML treatments.

DOI: https://doi.org/10.1182/bloodadvances.2025015806
Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]

Principles of cotranslational mitochondrial protein import.

Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.

  Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.

Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling

DOI:  https://doi.org/10.1016/j.cell.2025.07.021
Elife. 2025 Aug 13. pii: RP105318. [Epub ahead of print]14

PRMT1-mediated metabolic reprogramming promotes leukemogenesis.

Hairui Su, Yong Sun, Han Guo, Chiao-Wang Sun, Qiuying Chen, Szumam Liu, Anlun Li, Min Gao, Rui Zhao, Glen Raffel, Jian Jin, Cheng-Kui Qu, Michael Yu, Christopher A Klug, George Y Zheng, Scott Ballinger, Matthew Kutny, Long X Zheng, Zechen Chong, Chamara Senevirathne, Steven Gross, Yabing Chen, Minkui Luo, Xinyang Zhao.

  Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate and decreased the oxygen consumption rate. Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by fluorescence-activated cell sorting analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analog 2-deoxy-D-glucose delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. .

Keywords:  CPT1A; PRMT1; cancer biology; cell biology; fatty acids; glycolysis; leukemia; mitochondria; mouse

DOI:  https://doi.org/10.7554/eLife.105318
Cancer Sci. 2025 Aug 11.

Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML.

Jingmei Li, Emi Sugimoto, Keita Yamamoto, Yutong Dai, Wenyu Zhang, Yu-Hsuan Chang, Jakushin Nakahara, Tomohiro Yabushita, Toshio Kitamura, Sung-Joon Park, Kenta Nakai, Susumu Goyama.

  Although mTOR signaling plays a key role in acute myeloid leukemia (AML), mTOR inhibitors have shown limited efficacy against AML in clinical trials. In this study, we found that the anti-leukemic effect of mTOR inhibition was mediated in part through the TP53 pathway. mTOR inhibition by rapamycin and TP53 activation by DS-5272 collaboratively induced the downregulation of MYC and MCL1 partly through miR-34a, thereby inducing cell cycle arrest and apoptosis in AML cells. Joint non-negative matrix factorization (JNMF) and statistical regression analysis using public AML databases revealed that monocytic AMLs with distinctive gene expression profiles were highly sensitive to mTOR inhibition, leading to the generation of an 11-gene score (Rapa-11) to predict the rapamycin sensitivity of each monocytic AML. Consistent with our in silico prediction, mouse AML cells expressing MLL-AF9, the monocytic AML with a low Rapa-11 score, were highly sensitive to rapamycin, whereas those expressing RUNX1-ETO or SETBP1/ASXL1 mutations were not. Co-treatment with rapamycin and DS-5272 had a dramatic in vivo effect on MLL-AF9-driven AML, curing 85% of the leukemic mice. Thus, machine learning-based predictive approaches identified monocytic AML with wild-type TP53 and low Rapa-11 score as a rapamycin-sensitive AML subtype and an ideal target for mTOR/p53 co-targeting therapy.

Keywords:  TP53 ; acute myeloid leukemia; joint non‐negative matrix factorization; mTOR; machine learning

DOI:  https://doi.org/10.1111/cas.70170
IEEE Control Syst Lett. 2024 ;8 2205-2210

A Moments-Based Analytical Approach for Cell Size Homeostasis.

César Nieto, Cesar Augusto Vargas-Garcia, Abhyudai Singh.

  This contribution explores mechanisms that regulate the dynamics of single-cell size, maintaining equilibrium around a target set point. Using the formalism of Stochastic Hybrid Systems (SHS), we consider continuous exponential growth in cell size (as determined by volume/mass/surface area). This continuous-time evolution is interspersed by cell division events that occur randomly as per a given size-dependent rate, and upon division, only one of the two daughter cells is tracked. We show that a size-independent division rate does not provide cell size homeostasis, in the sense that the variance in cell size increases unboundedly over time. Next, we consider a division rate proportional to cell size that yields the adder size control observed in several bacteria - a constant size is added on average between birth and division regardless of the newborn size. For this scenario, we obtain exact formulas for the steady-state moments (mean, variance, and skewness) of cell size. Expanding the SHS model, we explore a biologically relevant scenario where the time between successive division events is further divided into multiple discrete stages with size-dependent stage transitions. Exact moment computations demonstrate that increasing the number of stages reduces cell size variability (noise). We also find formulas considering uneven size partitioning between daughters during division, and where the division rate follows a power law of the cell size leading to deviations from adder size control. This letter provides a method for estimating model parameters from observed cell size distributions and enhances our understanding of mechanisms underlying cell size regulation.

Keywords:  Systems biology; hybrid systems; stochastic systems

DOI:  https://doi.org/10.1109/lcsys.2024.3411041
Nat Commun. 2025 Aug 12. 16(1): 7482

Complementary cytoskeletal feedback loops control signal transduction excitability and cell polarity.

Jonathan Kuhn, Parijat Banerjee, Andrew Haye, Douglas N Robinson, Pablo A Iglesias, Peter N Devreotes.

To navigate complex environments, cells integrate chemical and mechanical cues through dynamic feedback between signaling networks and the cytoskeleton. Using synthetic tools to manipulate cytoskeletal components in Dictyostelium and human neutrophils, we uncover feedback mechanisms that regulate Ras/PI3K signaling and control front- and back-states of the cell. Increased branched actin and actin polymerization enhance Ras/PI3K activity. Similarly, decreased myosin II assembly also elevates signaling and chemotactic sensitivity. Conversely, inhibiting branched actin increases cortical actin and blocks Ras/PI3K activation-an effect lessened by decreasing filamentous actin or in myosin II-null cells. Activating RacE to increase actin crosslinking suppresses Ras activity without triggering branched actin nucleators, yet promotes spreading and protrusion. These results informed a computational model incorporating positive cytoskeletal feedback loops, which predicts shifts in polarity and migration with cytoskeletal changes. We propose that such feedback locally tunes signal network excitability, enabling cells to navigate tissues, extracellular matrix, and fluid environments.

DOI: https://doi.org/10.1038/s41467-025-62799-3
Free Radic Biol Med. 2025 Aug 13. pii: S0891-5849(25)00876-7. [Epub ahead of print]

HDAC Inhibition Protects RPE Cells from Oxidative Stress via Enhanced Mitochondrial Fusion, Cytoskeletal Repair, and Nrf-2 Activation.

Yarine Lugassy, Eva Berent, Lotan Tarnoy, Sandra Jeries, Tamar Ziv, Naphtali Savion, Hagit Eldar-Finkelman.

  Oxidative stress is a key driver of retinal pigment epithelium (RPE) damage and the development of age-related macular degeneration (AMD). Here, we demonstrate that the histone deacetylase (HDAC) inhibitors vorinostat and trichostatin A (TSA) elicit a coordinated cytoprotective response in RPE cells exposed to rotenone. Both compounds significantly reduced reactive oxygen species (ROS) levels, enhanced mitochondrial fusion, increased mitochondrial ATP production, and improved cell morphology and cell survival in the rotenone-treated cells. In addition, the compounds activated Nrf-2 as evidenced by Keap1 downregulation, increased p62/SQSTM1 expression, and induction of Nrf-2 targets, including heme oxygenase 1 (HO-1). Proteomic analysis of drug-treated cells revealed a significant enrichment of proteins involved in cytoskeletal organization and dynamics. Consistently, specific staining for actin filaments confirmed that vorinostat and TSA preserved cytoskeletal architecture and increased levels of the tight junction protein TJP3 in cells exposed to rotenone. Finally, inhibition of the vorinostat/TSA target HDAC6, or blockade of α-tubulin acetyltransferase, demonstrated that modulation of α-tubulin acetylation could influence ROS levels. Similarly, enhanced mitochondrial fusion by Mdivi-1 reduced ROS accumulation in the rotenone-treated cells. However, these last two interventions did not fully recapitulate the antioxidant effects observed with vorinostat or TSA. Our results identify a multifaceted protective mechanism triggered by HDAC inhibition in oxidatively stressed RPE cells and support the therapeutic repurposing of vorinostat in oxidative stress-driven RPE or retinal degeneration.

Keywords:  Age-related macular degeneration (AMD); Cytoskeleton; HDAC inhibitors; Mitochondrial dynamics; Nrf-2 signaling; Oxidative stress; Proteomics; Retinal pigment epithelium (RPE); Vorinostat

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.007