bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–02–09
twenty-two papers selected by
William Grey, University of York
  1. KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and non-canonical NFκB signaling at a steady state.
  2. Methodological Considerations on How to Identify Human Hematopoietic Stem Cells.
  3. Regulation of hematopoietic stem cell (HSC) proliferation by Epithelial Growth Factor Like-7 (EGFL7).
  4. Dynamic activity of Erg promotes aging of the hematopoietic system.
  5. Hematopoietic stem cell discovery: unveiling the historical and future perspective of colony-forming units assay.
  6. Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
  7. PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.
  8. Towards deciphering the bone marrow microenvironment with spatial multi-omics.
  9. SNORD113-114 cluster maintains haematopoietic stem cell self-renewal via orchestrating the translation machinery.
  10. Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma.
  11. Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to High-risk Behavior, in Multiple Myeloma.
  12. Formaldehyde Fixation Helps Preserve the Proteome State during Single-Cell Proteomics Sample Processing and Analysis.
  13. Phospho-seq: integrated, multi-modal profiling of intracellular protein dynamics in single cells.
  14. Biology and Management of Acute Myeloid Leukemia With Mutated NPM1.
  15. Context and timing matters in acute myeloid leukemia: females are the superior hosts.
  16. The autophagy component LC3 regulates lymphocyte adhesion via LFA1 transport in response to outside-in signaling.
  17. Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.
  18. Myeloma cell-derived CXCL7 facilitates proliferation of tumor cells and occurrence of osteolytic lesions through JAK/STAT3 pathway.
  19. The transmembrane protein Syndecan is required for stem cell survival and maintenance of their nuclear properties.
  20. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
  21. Liquid-like condensates that bind actin promote assembly and bundling of actin filaments.
  22. Pediatric AML: state of the Art and Future Directions.
  1. Exp Hematol. 2025 Feb 01. pii: S0301-472X(25)00021-9. [Epub ahead of print] 104730
    KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and non-canonical NFκB signaling at a steady state.
    Chun Shik Park, Cory S Bridges, Andrew H Lewis, Taylor J Chen, Saptarsi Shai, Wa Du, Monica Puppi, Barry Zorman, Sumazin Pavel, H Daniel Lacorazza.
      The transcription factor Krüppel-like factor 4 (KLF4) acts as a transcriptional activator and repressor. KLF4 plays a role in various cellular processes, including the dedifferentiation of somatic cells into induced pluripotent stem cells. Although it has been shown to enhance self-renewal in embryonic and leukemia stem cells, its role in adult hematopoietic stem cells (HSC) remains underexplored. We demonstrate that conditional deletion of the Klf4 gene in hematopoietic cells led to an increased frequency of immunophenotypic hematopoietic stem cells (HSCs) in the bone marrow, along with a normal distribution of lymphoid and myeloid progenitor cells. Non-competitive bone marrow transplants showed normal engraftment and multi-lineage reconstitution, except for monocytes and T cells. However, the loss of KLF4 hindered hematological reconstitution in competitive serial bone marrow transplants, highlighting a critical role for KLF4 in stress-induced hematopoiesis. Transcriptome analysis revealed an upregulation of NFκB2 and toll-like receptors (e.g., TLR4) in Klf4-null HSCs during homeostasis. Flow cytometry and immunoblot analysis confirmed the increased cell surface expression of TLR4 and the activation of NFκB2 in HSCs under homeostatic conditions, whereas NFκB2 expression drops after radiation compared to steady-state levels. Our findings suggest that the constitutive activation of the TLR4-NFκB2 pathway inhibits the ability of HSCs to regenerate blood after transplantation in cytoablated bone marrow.
    Keywords:  KLF4; bone marrow; hematopoietic stem cells; self-renewal
    DOI:  https://doi.org/10.1016/j.exphem.2025.104730
  2. Exp Hematol. 2025 Jan 30. pii: S0301-472X(25)00020-7. [Epub ahead of print] 104729
    Methodological Considerations on How to Identify Human Hematopoietic Stem Cells.
    Taylor Hinchly, Dominique Bonnet, Fernando Anjos-Afonso.
      Recently, human CD34+ hematopoietic stem cells (HSCs) have been purified to a frequency of approximately 1 in 3 cells, a population denoted as CD34+CD38-CD45RA-CD90±EPCR+ HSCs. This work aimed to evaluate the methodology for CD34+ HSC isolation, exploring differences in antibody clones, conjugates, source of cells and additional cell surface antigens (integrin-α6, CLEC9A and GPRC5C) to enhance the purity of these EPCR+ HSCs. We are emphasizing here the importance of experimental planning and antibody panel selection concerning the isolation of these human HSCs from multiple sources and providing important notes on the pitfalls of the reagents used for such purposes. Our results should enable a better reproducibility of results between labs, as well as further pursue work towards improving the enrichment of human HSCs.
    Keywords:  human hematopoietic stem cell markers; identification methods; methodology
    DOI:  https://doi.org/10.1016/j.exphem.2025.104729
  3. bioRxiv. 2025 Jan 23. pii: 2025.01.21.634107. [Epub ahead of print]
    Regulation of hematopoietic stem cell (HSC) proliferation by Epithelial Growth Factor Like-7 (EGFL7).
    Rohan Kulkarni, Chinmayee Goda, Alexander Rudich, Malith Karunasiri, Amog P Urs, Yaphet Bustos, Ozlen Balcioglu, Wenjun Li, Sadie Chidester, Kyleigh A Rodgers, Elizabeth Ar Garfinkle, Ami Patel, Katherine E Miller, Phillip G Popovich, Shannon Elf, Ramiro Garzon, Adrienne M Dorrance.
      Understanding the pathways regulating normal and malignant hematopoietic stem cell (HSC) biology is important for improving outcomes for patients with hematologic disorders. Epithelial Growth Factor Like-7 (EGFL7 ) is ∼30 kDa secreted protein that is highly expressed in adult HSCs. Using Egfl7 genetic knock-out ( Egfl7 KO) mice and recombinant EGFL7 (rEGFL7) protein, we examined the role of Egfl7 in regulating normal hematopoiesis. We found that Egfl7 KO mice had decreases in overall BM cellularity resulting in significant reduction in the number of hematopoietic stem and progenitor cells (HSPCs), which was due to dysregulation of normal cell-cycle progression along with a corresponding increase in quiescence. rEGFL7 treatment rescued our observed hematopoietic defects of Egfl7 KO mice and enhanced HSC expansion after genotoxic stress such as 5-FU and irradiation. Furthermore, treatment of WT mice with recombinant EGFL7 (rEGFL7) protein expands functional HSCs evidenced by an increase in transplantation potential. Overall, our data demonstrates a role for EGFL7 in HSC expansion and survival and represents a potential strategy for improving transplant engraftment or recovering bone marrow function after stress.
    DOI:  https://doi.org/10.1101/2025.01.21.634107
  4. bioRxiv. 2025 Jan 23. pii: 2025.01.23.634563. [Epub ahead of print]
    Dynamic activity of Erg promotes aging of the hematopoietic system.
    Mayuri Tanaka-Yano, Wade W Sugden, Dahai Wang, Brianna Badalamenti, Parker Côté, Diana Chin, Julia Goldstein, Stephan George, Gabriela F Rodrigues-Luiz, Edroaldo Lummertz da Rocha, Hojun Li, Trista E North, Berkley E Gryder, R Grant Rowe.
      Hematopoiesis changes to adapt to the physiology of development and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts over the lifespan is unknown. Here, we show that expression of the ETS family TF Erg is adult-biased, and that programmed upregulation of Erg expression during juvenile to adult aging is evolutionarily conserved and required for complete implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs, and persistent juvenile phenotypes in Erg haploinsufficient mice are dependent on deregulation of the fetal-biased TF Hmga2 . Finally, Erg haploinsufficiency in the adult results in fetal-like resistance to leukemogenesis. Overall, we identify a mechanism whereby HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.
    SUMMARY: The hematopoietic system undergoes a process of coordinated aging from the juvenile to adult states. Here, we find that expression of ETS family transcription factor Erg is temporally regulated. Impaired upregulation of Erg during the hematopoietic maturation results in persistence of juvenile phenotypes.
    DOI:  https://doi.org/10.1101/2025.01.23.634563
  5. PeerJ. 2025 ;13 e18854
    Hematopoietic stem cell discovery: unveiling the historical and future perspective of colony-forming units assay.
    Nur Afizah Yusoff, Zariyantey Abd Hamid, Siti Balkis Budin, Izatus Shima Taib.
      Stem cells are special cells with the distinctive capability to self-renew, forming a new pool of undifferentiated stem cells. They are also able to differentiate into lineage-specific cell types that are specialized and matured. Thus, stem cells are considered as the building blocks of tissues and organs in which they reside. Among the many types of stem cells, hematopoietic stem cells (HSCs) are the most studied adult stem cells and are considered as a promising source of cells for applications in the clinical and basic sciences. Historically, research on HSCs was initiated in the 1940s, where in a groundbreaking experiment, intravenously injected bone marrow (BM) cells prevented the death of irradiated mice by restoring blood cell production. Since then, HSCs have been studied and utilized in medical therapies and research for over several decades. Over time, more sophisticated tools have been developed to evaluate the behaviour of specifically purified subsets of hematopoietic cells that have the capacity to produce blood cells. One of the established tools is the colony-forming units (CFUs) assay. This assay facilitates the identification, enumeration, and analysis of colonies formed by differentiated hematopoietic stem and progenitor cells (HSPCs) from myeloid, erythroid and lymphoid lineages. Hence, the CFUs assay is a fundamental in vitro platform that allows functional studies on the lineage potential of an individual HSPCs. The outcomes of such studies are crucial in providing critical insights into hematopoiesis. In this review, we explore the fundamental discoveries concerning the CFUs assay by covering the following aspects: (i) the historical overview of the CFUs assay for the study of clonal hematopoiesis involving multilineage potential of HSPCs, (ii) its use in various experimental models comprising humans, mice/rodents, zebrafish and induced pluripotent stem cells (iPSCs) and (iii) research gaps and future direction concerning the role of CFUs assay in clinical and basic sciences. Overall, the CFUs assay confers a transformative platform for a better understanding of HSPCs biology in governing hematopoiesis.
    Keywords:  Colony-forming unit; Hematopoiesis; Hematopoietic lineages; Hematopoietic stem and progenitor cells
    DOI:  https://doi.org/10.7717/peerj.18854
  6. Nat Commun. 2025 Feb 04. 16(1): 1358
    Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
    Xiaofan Sun, Yue Li, Juan Du, Fangshu Liu, Caiping Wu, Weihao Xiao, Guopan Yu, Xiaowei Chen, Robert Peter Gale, Hui Zeng.
      Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.
    DOI:  https://doi.org/10.1038/s41467-025-56520-7
  7. Blood. 2025 Feb 05. pii: blood.2024026040. [Epub ahead of print]
    PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.
    Lingli He, Ting Zhao, Wei Zhong Leong, Azeem Sharda, Christina Mayerhofer, Shenglin Mei, Gracia M Bonilla, Juan Bautista Menendez-Gonzalez, Karin Gustafsson, Tsuyoshi Fukushima, Trine A Kristiansen, Ji-Won Lee, Yanxin Xu, Lei Chen, Jun Xia, Luis Angel Orozco, Bogdan Budnik, Ruslan Sadreyev, Zhixun Dou, David B Sykes, David T Scadden.
      Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.
    DOI:  https://doi.org/10.1182/blood.2024026040
  8. Semin Cell Dev Biol. 2025 Jan 30. pii: S1084-9521(25)00006-0. [Epub ahead of print]167 10-21
    Towards deciphering the bone marrow microenvironment with spatial multi-omics.
    Raymond K H Yip, Edwin D Hawkins, Rory Bowden, Kelly L Rogers.
      The tissue microenvironment refers to a localised tissue area where a complex combination of cells, structural components, and signalling molecules work together to support specific biological activities. A prime example is the bone marrow microenvironment, particularly the hematopoietic stem cell (HSC) niche, which is of immense interest due to its critical role in supporting lifelong blood cell production and the growth of malignant cells. In this review, we summarise the current understanding of HSC niche biology, highlighting insights gained from advanced imaging and genomic techniques. We also discuss the potential of emerging technologies such as spatial multi-omics to unravel bone marrow architecture in unprecedented detail.
    Keywords:  Bone marrow; Genomics; Hematopoiesis; Imaging; Microenvironment; Niche; Spatial omics
    DOI:  https://doi.org/10.1016/j.semcdb.2025.01.001
  9. Nat Cell Biol. 2025 Jan 31.
    SNORD113-114 cluster maintains haematopoietic stem cell self-renewal via orchestrating the translation machinery.
    Hui Wang, Zhaoru Zhang, Chenxi Han, Penglei Jiang, Jiayue Xu, Yingli Han, Deyu Huang, Jian Li, Jie Zhou, Michael Durnin, Shiyuan Chen, Yaxin Liu, Jinghao Sheng, Jie Cao, Jianzhao Liu, Bing Liu, Jia Yu, Fang Wang, Pengxu Qian.
      Haematopoietic stem cells (HSCs) self-renew and differentiate to replenish the pool of blood cells, which require a low but finely tuned protein synthesis rate. Nonetheless, the translatome landscape in HSCs and how the translation machinery orchestrates HSC self-renewal remain largely elusive. Here we perform ultra-low-input Ribo-seq in HSCs, progenitor and lineage cells, and reveal HSC-specific translated genes involved in rRNA processing. We systematically profile small nucleolar RNAs (snoRNAs) and uncover an indispensable role of the SNORD113-114 cluster in regulating HSC self-renewal. Maternal knockout (Mat-KO) of this cluster substantially impairs HSC self-renewal, whereas loss of the paternal allele shows no obvious phenotype. Mechanistically, Mat-KO results in dysregulation of translation machinery (rRNA 2'-O-Me modifications, pre-rRNA processing, 60S ribosome assembly and translation) and induces nucleolar stress in HSCs, which exempts p53 from Mdm2-mediated proteasomal degradation and leads to apoptosis. Collectively, our study provides a promising facet to our understanding of snoRNA-mediated regulation in HSC homeostasis.
    DOI:  https://doi.org/10.1038/s41556-024-01593-7
  10. Sci Immunol. 2025 Feb 07. 10(104): eadp6667
    Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma.
    Raphael Lutz, Alexandra M Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S Raab, Simon Haas, Niels Weinhold.
      The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow-confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.
    DOI:  https://doi.org/10.1126/sciimmunol.adp6667
  11. Blood. 2025 Feb 06. pii: blood.2024024781. [Epub ahead of print]
    Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to High-risk Behavior, in Multiple Myeloma.
    Li Qin, Luz Yurany Moreno Rueda, Upasana Ray, Iqbal Mahmud, Lin Tan, Philip L Lorenzi, Suyu Liu, Heather Yan Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Maria Jose Acevedo Calado, Hua Wang, Elisabet E Manasanch, Hans C Lee, Krina K Patel, Isere Kuiatse, David E Symer, Robert Z Orlowski.
      Plasma cell dyscrasias encompass a spectrum from the precursors monoclonal gammopathy of undetermined significance and smoldering myeloma to symptomatic myeloma, but the genes that enable progression and confer poor prognosis are incompletely understood. Using single cell transcriptomics, we identified the Caseinolytic protease proteolytic subunit (CLPP), a key component of the mitochondrial CLP serine endopeptidase, as being over-expressed in CD138+ neoplastic versus normal, and in symptomatic versus precursor plasma cells. Its high expression was associated with an adverse prognosis across multiple molecularly defined subgroups in the newly diagnosed and relapsed/refractory settings, and with extramedullary disease. Pharmacologic CLPP inhibition and genetic suppression reduced organoid growth, cell viability, and cell cycle progression, while triggering an unfolded protein response and apoptosis. This occurred in association with mitochondrial transmembrane potential loss, and caspase and proteasome activation in a reactive oxygen species-dependent manner. Downstream consequences included autophagy and mitophagy induction, and reductions in oxidative phosphorylation and glycolysis with consequent compromise of mitochondrial and cytoplasmic ATP production. CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes.
    DOI:  https://doi.org/10.1182/blood.2024024781
  12. J Proteome Res. 2025 Feb 03.
    Formaldehyde Fixation Helps Preserve the Proteome State during Single-Cell Proteomics Sample Processing and Analysis.
    Ilaria Piga, Claire Koenig, Maico Lechner, Pierre Sabatier, Jesper V Olsen.
      Mass spectrometry-based single-cell proteomics (SCP) is gaining momentum but remains limited to a few laboratories due to the high costs and specialized expertise required. The ability to send samples to specialized core facilities would benefit nonspecialist laboratories and popularize SCP for biological applications. However, no methods have been tested in SCP to "freeze" the proteome state while maintaining cell integrity for transfer between laboratories or prolonged sorting using fluorescence-activated cell sorting (FACS). This study evaluates whether short-term formaldehyde (FA) fixation can maintain the cell states. We demonstrate that short-term FA fixation does not substantially affect protein recovery, even without heating and strong detergents, and maintains analytical depth compared with classical workflows. Fixation also preserves drug-induced specific perturbations of the protein abundance during cell sorting and sample preparation for SCP analysis. Our findings suggest that FA fixation can facilitate SCP by enabling sample shipping and prolonged sorting, potentially democratizing access to SCP technology and expanding its application in biological research, thereby accelerating discoveries in cell biology and personalized medicine.
    Keywords:  One-Tip; cell-sorting; formaldehyde fixation; single-cell proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00656
  13. Nat Commun. 2025 Feb 04. 16(1): 1346
    Phospho-seq: integrated, multi-modal profiling of intracellular protein dynamics in single cells.
    John D Blair, Austin Hartman, Fides Zenk, Philipp Wahle, Giovanna Brancati, Carol Dalgarno, Barbara Treutlein, Rahul Satija.
      Cell signaling plays a critical role in neurodevelopment, regulating cellular behavior and fate. While multimodal single-cell sequencing technologies are rapidly advancing, scalable and flexible profiling of cell signaling states alongside other molecular modalities remains challenging. Here we present Phospho-seq, an integrated approach that aims to quantify cytoplasmic and nuclear proteins, including those with post-translational modifications, and to connect their activity with cis-regulatory elements and transcriptional targets. We utilize a simplified benchtop antibody conjugation method to create large custom neuro-focused antibody panels for simultaneous protein and scATAC-seq profiling on whole cells, alongside both experimental and computational strategies to incorporate transcriptomic measurements. We apply our workflow to cell lines, induced pluripotent stem cells, and months-old retinal and brain organoids to demonstrate its broad applicability. We show that Phospho-seq can provide insights into cellular states and trajectories, shed light on gene regulatory relationships, and help explore the causes and effects of diverse cell signaling in neurodevelopment.
    DOI:  https://doi.org/10.1038/s41467-025-56590-7
  14. Am J Hematol. 2025 Feb 04.
    Biology and Management of Acute Myeloid Leukemia With Mutated NPM1.
    Evan C Chen, Shai Shimony, Marlise R Luskin, Richard M Stone.
      Mutations in nucleophosmin 1 (NPM1) are diseased-defining genetic alterations encountered in approximately one-third of cases of acute myeloid leukemia (AML). A mutation in NPM1 confers a more favorable prognosis; however, clinical outcomes of NPM1-mutated AML (NPM1mut AML) are diverse due to the heterogeneity of disease biology, patient characteristics, and treatment received. Research over the last two decades has dramatically expanded our understanding of the biology of NPM1mut AML and led to the development of new therapeutic approaches and strategies for monitoring measurable residual disease (MRD). Here, we review NPM1mut AML with a practical focus on the current treatment landscape, the role of MRD in guiding management, and emerging therapies, including menin inhibitors.
    Keywords:  AML; AML‐molecular diagnosis & therapy; dysplasias; neoplasia‐myeloid leukemias
    DOI:  https://doi.org/10.1002/ajh.27600
  15. Haematologica. 2025 Feb 06.
    Context and timing matters in acute myeloid leukemia: females are the superior hosts.
    Kerstin B Kaufmann, Stephanie Z Xie.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.287056
  16. Nat Commun. 2025 Feb 04. 16(1): 1343
    The autophagy component LC3 regulates lymphocyte adhesion via LFA1 transport in response to outside-in signaling.
    Naoyuki Kondo, Yuko Mimori-Kiyosue, Keizo Tokuhiro, Giuseppe Pezzotti, Tatsuo Kinashi.
      The leukocyte integrin LFA1 is indispensable for immune responses, orchestrating lymphocyte trafficking and adhesion. While LFA1 activation induces LFA1 clustering at the cell contact surface via outside-in signaling, the regulatory mechanisms remain unclear. Here, we uncovered a previously hidden function of the autophagosome component LC3 beyond its role in autophagy by bridging two seemingly unrelated pathways: LFA1 transport and autophagosome transport. LFA1 clusters co-trafficked with LC3, facilitating LFA1 accumulation at the contact surface. LC3b knockout decreased lymphocyte adhesiveness. LFA1 activation did not induce autophagy, whereas it increased mTOR and AMPK activity. LFA1-dependent AMPK activation enhances LFA1 and LC3 clustering and adhesion. Inhibiting Mst1 kinase-mediated LC3 phosphorylation promoted LC3-mediated LFA1 recruitment to the contact surface through direct interaction with RAPL, uncovering an unprecedented integrin recruitment route. These findings uncover a function of LC3 and expand our understanding of lymphocyte regulation via LFA1.
    DOI:  https://doi.org/10.1038/s41467-025-56631-1
  17. Nat Aging. 2025 Feb 05.
    Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.
    Rabia R Khawaja, Adrián Martín-Segura, Olaya Santiago-Fernández, Rebecca Sereda, Kristen Lindenau, Mericka McCabe, Adrián Macho-González, Maryam Jafari, Aurora Scrivo, Raquel Gomez-Sintes, Bhakti Chavda, Ana Rosa Saez-Ibanez, Inmaculada Tasset, Esperanza Arias, Xianhong Xie, Mimi Kim, Susmita Kaushik, Ana Maria Cuervo.
      Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
    DOI:  https://doi.org/10.1038/s43587-024-00799-6
  18. Cell Death Dis. 2025 Feb 06. 16(1): 74
    Myeloma cell-derived CXCL7 facilitates proliferation of tumor cells and occurrence of osteolytic lesions through JAK/STAT3 pathway.
    Yue Wang, Tianwei Lan, Qiongyan Zhang, Chi Zhou, Peng Liu.
      Osteolytic lesions and pathological fractures are hallmark manifestations of multiple myeloma (MM), profoundly influencing the quality of life and self-care ability of MM patients. By analyzing transcriptome data and single-cell RNA-seq data from our center and the GEO database, a subset of MM cells with high expression levels of chemokine CXCL7 was identified. This subset of MM cells possesses a high capacity for proliferation and activation of osteoclast signaling pathway. CXCL7 might be a crucial regulator of osteolytic damage in MM. Subsequently, the association between the expression level of CXCL7 and pathological fractures in patients was investigated, and the impact of CXCL7 on MM proliferation was confirmed both in vivo and in vitro. A mouse xenograft tumor model was established through intravenous injection of myeloma cell lines based on the homing ability of plasma cells. Moreover, the mechanism by which CXCL7 promotes the activation of osteoclast signaling pathways in MM was explored. Our findings reveal that elevated CXCL7 levels significantly enhance MM cell proliferation, increasing the risk of pathological fractures in MM patients. Additionally, our mouse xenograft tumor model demonstrated that CXCL7 can induce femoral fractures and reduce bone mineral density. Concurrently, it was discovered that CXCL7 could activate the JAK/STAT3 pathway via CXCR2 and upregulate the expression levels of MMP13 and C-myc, facilitating MM cell proliferation and activation of the osteoclast signaling pathway. Our study offers novel insights into the pathogenic mechanism of osteolytic lesions and implies that targeting CXCL7 may present a new therapeutic avenue for MM.
    DOI:  https://doi.org/10.1038/s41419-025-07413-6
  19. PLoS Genet. 2025 Feb 06. 21(2): e1011586
    The transmembrane protein Syndecan is required for stem cell survival and maintenance of their nuclear properties.
    Buffy L Eldridge-Thomas, Jerome G Bohere, Chantal Roubinet, Alexandre Barthelemy, Tamsin J Samuels, Felipe Karam Teixeira, Golnar Kolahgar.
      Tissue maintenance is underpinned by resident stem cells whose activity is modulated by microenvironmental cues. Using Drosophila as a simple model to identify regulators of stem cell behaviour and survival in vivo, we have identified novel connections between the conserved transmembrane proteoglycan Syndecan, nuclear properties and stem cell function. In the Drosophila midgut, Syndecan depletion in intestinal stem cells results in their loss from the tissue, impairing tissue renewal. At the cellular level, Syndecan depletion alters cell and nuclear shape, and causes nuclear lamina invaginations and DNA damage. In a second tissue, the developing Drosophila brain, live imaging revealed that Syndecan depletion in neural stem cells results in nuclear envelope remodelling defects which arise upon cell division. Our findings reveal a new role for Syndecan in the maintenance of nuclear properties in diverse stem cell types.
    DOI:  https://doi.org/10.1371/journal.pgen.1011586
  20. Nat Commun. 2025 Feb 06. 16(1): 1406
    ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
    Shiyang Wang, Xi Wu, Wenxin Bi, Jiuzhi Xu, Liyuan Hou, Guilin Li, Yuwei Pan, Hanfu Zhang, Mengzhen Li, Sujuan Du, Mingxin Zhang, Di Liu, Shuiling Jin, Xiaojing Shi, Yuhua Tian, Jianwei Shuai, Maksim V Plikus, Moshi Song, Zhaocai Zhou, Lu Yu, Cong Lv, Zhengquan Yu.
      Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-56444-2
  21. Dev Cell. 2025 Feb 04. pii: S1534-5807(25)00032-2. [Epub ahead of print]
    Liquid-like condensates that bind actin promote assembly and bundling of actin filaments.
    Caleb Walker, Aravind Chandrasekaran, Daniel Mansour, Kristin Graham, Andrea Torres, Liping Wang, Eileen M Lafer, Padmini Rangamani, Jeanne C Stachowiak.
      Biomolecular condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that assemble and bundle actin. Here, we show that this behavior does not require proteins with specific polymerase activity. Specifically, condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of assembling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds filamentous actin could bundle filaments through multivalent crosslinking. To test this, we added a filamentous-actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that facilitated efficient assembly and bundling of actin filaments. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any filamentous-actin-binding protein that participates in protein condensation.
    Keywords:  Lamellipodin; VASP; actin cytoskeleton; agent-based modeling; biomolecular condensates; multivalent interactions; protein phase separation
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.012
  22. Pediatr Hematol Oncol. 2025 Jan 31. 1-20
    Pediatric AML: state of the Art and Future Directions.
    Prasad Iyer.
      Pediatric acute myeloid leukemia (AML) is a heterogeneous and aggressive hematological malignancy. Despite advances in treatment, the survival rates remain unsatisfactory, emphasizing the need for innovative therapeutic approaches. This narrative review presents a comprehensive overview of the current approach and likely future directions for pediatric AML. The distinct genetic, epigenetic, and molecular features of pediatric AML contribute to its complex pathophysiology and impact on prognosis. Current treatment practices involve a multifaceted approach combining chemotherapy, molecularly targeted therapies, and hematopoietic stem cell transplantation. However, intensive treatment often leads to significant acute and long-term toxicity. Emerging strategies, including precision medicine, immunotherapy, and novel agents, hold promise for improving outcomes and minimizing adverse effects. Ongoing clinical trials are investigating the potential of these innovative approaches to transform pediatric AML care. By highlighting the evolving treatment paradigms and future perspectives, this review underscores the importance of continued research and development in pediatric AML to enhance the survival rates and quality of life of these young patients.
    Keywords:  Hematopoietic stem cell transplantation; immunotherapy; molecular diagnostics; pediatric acute myeloid leukemia; precision medicine; targeted therapies
    DOI:  https://doi.org/10.1080/08880018.2025.2453861
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