bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–08–25
twenty-two papers selected by
William Grey, University of York
  1. Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
  2. The role of the hematopoietic stem/progenitor cells-derived extracellular vesicles in hematopoiesis.
  3. Ing4-deficiency promotes a quiescent yet transcriptionally poised state in hematopoietic stem cells.
  4. Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia.
  5. RNA binding protein-directed control of leukemic stem cell evolution and function.
  6. Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice.
  7. Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties.
  8. Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.
  9. Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.
  10. Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.
  11. Prediction of CD34+ hematopoietic stem cells in healthy allogeneic stem cell donors on the Optia cell separator based on CE2: Which formula is more correlated with actual CD34+?
  12. Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML).
  13. Genetic code expansion, click chemistry, and light-activated PI3K reveal details of membrane protein trafficking downstream of receptor tyrosine kinases.
  14. Compression-dependent microtubule reinforcement enables cells to navigate confined environments.
  15. Glycolysis and chemoresistance in acute myeloid leukemia.
  16. Efficient generation of human immune system rats using human CD34+ cells.
  17. Venetoclax for pediatric patients with newly diagnosed acute myeloid leukemia.
  18. miR-149-3p Enhances Drug Sensitivity of AML Cells by Inhibiting Warburg Effect Through PI3K/AKT Pathway.
  19. Recent advances in AML with mutated NPM1.
  20. Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics.
  21. Substrate stiffness alters layer architecture and biophysics of human induced pluripotent stem cells to modulate their differentiation potential.
  22. Coordination of force-generating actin-based modules stabilizes and remodels membranes in vivo.
  1. Sci Immunol. 2024 Aug 23. 9(98): eadk3469
    Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
    Merve Aksöz, Grigore-Aristide Gafencu, Bilyana Stoilova, Mario Buono, Ying Zhang, Sven Turkalj, Yiran Meng, Niels Asger Jakobsen, Marlen Metzner, Sally-Ann Clark, Ryan Beveridge, Supat Thongjuea, Paresh Vyas, Claus Nerlov.
      Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.
    DOI:  https://doi.org/10.1126/sciimmunol.adk3469
  2. Heliyon. 2024 Aug 15. 10(15): e35051
    The role of the hematopoietic stem/progenitor cells-derived extracellular vesicles in hematopoiesis.
    Ezzatollah Fathi, Behnaz Valipour, Sevda Jafari, Abdolhassan Kazemi, Soheila Montazersaheb, Raheleh Farahzadi.
      Hematopoietic stem cells (HSCs) are tightly regulated by specific microenvironments called niches to produce an appropriate number of mature blood cell types. Self-renewal and differentiation are two hallmarks of hematopoietic stem and progenitor cells, and their balance is critical for proper functioning of blood and immune cells throughout life. In addition to cell-intrinsic regulation, extrinsic cues within the bone marrow niche and systemic factors also affect the fate of HSCs. Despite this, many paracrine and endocrine factors that influence the function of hematopoietic cells remain unknown. In hematological malignancies, malignant cells remodel their niche into a permissive environment to enhance the survival of leukemic cells. These events are accompanied by loss of normal hematopoiesis. It is well known that extracellular vehicles (EVs) mediate intracellular interactions under physiological and pathological conditions. In other words, EVs transfer biological information to surrounding cells and contribute not only to physiological functions but also to the pathogenesis of some diseases, such as cancers. Therefore, a better understanding of cell-to-cell interactions may lead to identification of potential therapeutic targets. Recent reports have suggested that EVs are evolutionarily conserved constitutive mediators that regulate hematopoiesis. Here, we focus on the emerging roles of EVs in normal and pathological conditions, particularly in hematological malignancies. Owing to the high abundance of EVs in biological fluids, their potential use as biomarkers and therapeutic tools is discussed.
    Keywords:  Biomarkers; Extracellular vesicles; Hematological malignancies; Hematopoiesis
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e35051
  3. iScience. 2024 Aug 16. 27(8): 110521
    Ing4-deficiency promotes a quiescent yet transcriptionally poised state in hematopoietic stem cells.
    Zanshé Thompson, Georgina A Anderson, Marco Hernandez, Carlos Alfaro Quinde, Alissa Marchione, Melanie Rodriguez, Seth Gabriel, Vera Binder, Alison M Taylor, Katie L Kathrein.
      Defining the mechanisms that regulate stem cell maintenance, proliferation, and differentiation is critical for identifying therapies for improving stem cell function under stress. Here, we have identified the tumor suppressor, inhibitor of growth 4 (Ing4), as a critical regulator of hematopoietic stem cell (HSC) homeostasis. Cancer cell line models with Ing4 deficiency have shown that Ing4 functions as a tumor suppressor, in part, due to Ing4-mediated regulation of several major signaling pathways, including c-Myc. In HSCs, we show Ing4 deficiency promotes gene expression signatures associated with activation, yet HSCs are arrested in G0, expressing several markers of quiescence. Functionally, Ing4-deficient HSCs demonstrate robust regenerative capacity following transplantation. Our findings suggest Ing4 deficiency promotes a poised state in HSCs, where they appear transcriptionally primed for activation but remain in a resting state. Our model provides key tools for further identification and characterization of pathways that control quiescence and self-renewal in HSCs.
    Keywords:  biological sciences; cell biology; natural sciences; specialized functions of cells; stem cell research
    DOI:  https://doi.org/10.1016/j.isci.2024.110521
  4. Blood. 2024 Aug 16. pii: blood.2023023644. [Epub ahead of print]
    Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia.
    Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu.
      Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.
    DOI:  https://doi.org/10.1182/blood.2023023644
  5. Hemasphere. 2024 Aug;8(8): e116
    RNA binding protein-directed control of leukemic stem cell evolution and function.
    Pratik Joshi, Ava Keyvani Chahi, Lina Liu, Steven Moreira, Ana Vujovic, Kristin J Hope.
      Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post-transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post-transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post-transcriptional control as actionable targets for precision therapy of AML.
    DOI:  https://doi.org/10.1002/hem3.116
  6. Mol Ther Nucleic Acids. 2024 Sep 10. 35(3): 102268
    Bi-functional CpG-STAT3 decoy oligonucleotide triggers multilineage differentiation of acute myeloid leukemia in mice.
    Dongfang Wang, Damian Kaniowski, Karol Jacek, Yu-Lin Su, Chunsong Yu, Jeremy Hall, Haiqing Li, Mingye Feng, Susanta Hui, Bożena Kaminska, Vittorio DeFranciscis, Carla Lucia Esposito, Annalisa DiRuscio, Bin Zhang, Guido Marcucci, Ya-Huei Kuo, Marcin Kortylewski.
      Acute myeloid leukemia (AML) cells resist differentiation stimuli despite high expression of innate immune receptors, such as Toll-like receptor 9 (TLR9). We previously demonstrated that targeting Signal Transducer and Activator of Transcription 3 (STAT3) using TLR9-targeted decoy oligodeoxynucleotide (CpG-STAT3d) increases immunogenicity of human and mouse AML cells. Here, we elucidated molecular mechanisms of inv(16) AML reprogramming driven by STAT3-inhibition/TLR9-activation in vivo. At the transcriptional levels, AML cells isolated from mice after intravenous administration of CpG-STAT3d or leukemia-targeted Stat3 silencing and TLR9 co-stimulation, displayed similar upregulation of myeloid cell differentiation (Irf8, Cebpa, Itgam) and antigen-presentation (Ciita, Il12a, B2m)-related genes with concomitant reduction of leukemia-promoting Runx1. Single-cell transcriptomics revealed that CpG-STAT3d induced multilineage differentiation of AML cells into monocytes/macrophages, erythroblastic and B cell subsets. As shown by an inducible Irf8 silencing in vivo, IRF8 upregulation was critical for monocyte-macrophage differentiation of leukemic cells. TLR9-driven AML cell reprogramming was likely enabled by downregulation of STAT3-controlled methylation regulators, such as DNMT1 and DNMT3. In fact, the combination of DNA methyl transferase (DNMT) inhibition using azacitidine with CpG oligonucleotides alone mimicked CpG-STAT3d effects, resulting in AML cell differentiation, T cell activation, and systemic leukemia regression. These findings highlight immunotherapeutic potential of bi-functional oligonucleotides to unleash TLR9-driven differentiation of leukemic cells by concurrent STAT3 and/or DNMT inhibition.
    Keywords:  CpG deoxynucleotides; MT: Oligonucleotides: Therapies and Applications; Oligonucleotide therapeutics; STAT3; TLR9; acute myeloid leukemia; cancer immunotherapy; decoy DNA
    DOI:  https://doi.org/10.1016/j.omtn.2024.102268
  7. Leukemia. 2024 Aug 21.
    Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties.
    Héléna Boutzen, Alex Murison, Alexa Oriecuia, Suraj Bansal, Christopher Arlidge, Jean C Y Wang, Mathieu Lupien, Kerstin B Kaufmann, John E Dick.
      The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.
    DOI:  https://doi.org/10.1038/s41375-024-02358-9
  8. Front Pharmacol. 2024 ;15 1409210
    Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.
    Monika Chomczyk, Luca Gazzola, Shubhankar Dash, Patryk Firmanty, Binsah S George, Vakul Mohanty, Hussein A Abbas, Natalia Baran.
      Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%-12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.
    Keywords:  AML; TP53 mutations; drug resistance; immunosuppression; metabolic rewiring; therapeutic approaches
    DOI:  https://doi.org/10.3389/fphar.2024.1409210
  9. Exp Hematol Oncol. 2024 Aug 16. 13(1): 84
    Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.
    Noelia Che, Sandra Cantilena, Remi Looi-Somoye, Danesh Sundar, Kent Fung, Jasper de Boer, Owen Williams.
      Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.
    Keywords:  Acute lymphoblastic leukemia; Acute myeloid leukemia,; KMT2A; MLL
    DOI:  https://doi.org/10.1186/s40164-024-00556-w
  10. Blood Adv. 2024 Aug 19. pii: bloodadvances.2024012879. [Epub ahead of print]
    Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.
    Theresa Landspersky, Merle Stein, Mehmet Saçma, Johanna Geuder, Krischan Braitsch, Jennifer Rivière, Franziska Hettler, Sandra Romero Marquez, Baiba Vilne, Erik Hameister, Daniel Richter, Emely Schönhals, Jan Tuckermann, Mareike Verbeek, Peter Herhaus, Judith S Hecker, Florian Bassermann, Katharina S Götze, Wolfgang Enard, Hartmut Geiger, Robert A J Oostendorp, Christina Schreck.
      Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs) that include skeletal progenitors from mice undergoing HSCT. Such MSPCs showed reduced CFU-F frequency, increased DNA damage and enhanced occurrence of cellular senescence, while there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small RhoGTPAse Cdc42, disorganized F-actin distribution, mitochondrial abnormalities and impaired mitophagy in MSPCs. Changes and defects similar to those in mice were also observed in MSPCs from humans undergoing HSCT. A pharmacological treatment that attenuated the elevated activation of CDC42 restored F-actin fiber alignment, mitochondrial function, and mitophagy in MSPCs in vitro. Finally, targeting CDC42 activity in vivo in animals undergoing transplants improved MSPC quality to increase both bone volume and trabecular bone thickness. Our study shows that attenuation of CDC42 activity is sufficient to attenuate reduced function of MSPCs in a BM transplant setting.
    DOI:  https://doi.org/10.1182/bloodadvances.2024012879
  11. Transfusion. 2024 Aug 17.
    Prediction of CD34+ hematopoietic stem cells in healthy allogeneic stem cell donors on the Optia cell separator based on CE2: Which formula is more correlated with actual CD34+?
    Sıdıka Gülkan Özkan, Ali Kimiaei, Seyedehtina Safaei, Tarık Ercan, Meral Sönmezoğlu, Gülderen Yanıkkaya Demirel, Sema Aktaş, Sinem Özdemir, Helin Serda Özalp, Hasan Atilla Özkan.
       BACKGROUND: Peripheral blood-derived hematopoietic stem cells (HSCs) are widely used for various adult stem cell transplants. To obtain sufficient HSCs from healthy volunteer donors during the apheresis process and ensure that the donors are exposed to fewer apheresis-related side effects, calculation methods have been developed for the prediction of processed blood volume or CD34+ count. However, there is no consensus on a formula to predict the volume of blood to be processed or the number of stem cells to be obtained.
    OBJECTIVE: This study aimed to estimate the predicted blood volume and CD34+ cell counts using collection efficiency (CE)-based formulas and evaluate their accuracy compared to the actual CD34+ cell counts. It also seeks to identify the factors that affect CE.
    METHODS: Data from 397 healthy, unrelated stem cell donors were retrospectively analyzed. An algorithm using four different CE2 metrics (1st quartile, mean, 3rd quartile, and median) was developed to predict the volume of blood to be processed using the Spectra Optia continuous mononuclear cell collection procedure.
    RESULTS: When employing the mean CE2 algorithm, the results revealed a strong correlation (r = .894, p < .001) between predicted and actual CD34+ values. The study also identified strong associations between pre-apheresis CD34+, pre-apheresis leukocyte count, the use of two doses of G-CSF, and low CE2.
    CONCLUSION: These findings suggest that the mean CE2 algorithm could be a potent, straightforward, and accurate tool for predicting CD34+ stem cell counts in healthy allogeneic stem cell donors and potentially optimizing stem cell collection procedures.
    Keywords:  CD34+ hematopoietic stem cells; Spectra Optia cell separator; apheresis; collection efficiency 2; prediction algorithms; stem cell transplantation
    DOI:  https://doi.org/10.1111/trf.17990
  12. Leukemia. 2024 Aug 21.
    Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML).
    Eduardo Rodríguez-Arbolí, Megan Othus, Sylvie D Freeman, Francesco Buccisano, Lok Lam Ngai, Ian Thomas, Raffaele Palmieri, Jacqueline Cloos, Sean Johnson, Elisa Meddi, Nigel H Russell, Adriano Venditti, Patrycja Gradowska, Gert J Ossenkoppele, Bob Löwenberg, Roland B Walter.
      
    DOI:  https://doi.org/10.1038/s41375-024-02378-5
  13. Elife. 2024 Aug 20. pii: RP91012. [Epub ahead of print]12
    Genetic code expansion, click chemistry, and light-activated PI3K reveal details of membrane protein trafficking downstream of receptor tyrosine kinases.
    Duk-Su Koh, Anastasiia Stratiievska, Subhashis Jana, Shauna C Otto, Teresa M Swanson, Anthony Nhim, Sara Carlson, Marium Raza, Ligia Araujo Naves, Eric N Senning, Ryan A Mehl, Sharona E Gordon.
      Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane.
    Keywords:  biochemistry; chemical biology; click chemistry; human; membrane protein; molecular biophysics; rat; structural biology; trafficking
    DOI:  https://doi.org/10.7554/eLife.91012
  14. Nat Cell Biol. 2024 Aug 19.
    Compression-dependent microtubule reinforcement enables cells to navigate confined environments.
    Robert J Ju, Alistair D Falconer, Christanny J Schmidt, Marco A Enriquez Martinez, Kevin M Dean, Reto P Fiolka, David P Sester, Max Nobis, Paul Timpson, Alexis J Lomakin, Gaudenz Danuser, Melanie D White, Nikolas K Haass, Dietmar B Oelz, Samantha J Stehbens.
      Cells migrating through complex three-dimensional environments experience considerable physical challenges, including tensile stress and compression. To move, cells need to resist these forces while also squeezing the large nucleus through confined spaces. This requires highly coordinated cortical contractility. Microtubules can both resist compressive forces and sequester key actomyosin regulators to ensure appropriate activation of contractile forces. Yet, how these two roles are integrated to achieve nuclear transmigration in three dimensions is largely unknown. Here, we demonstrate that compression triggers reinforcement of a dedicated microtubule structure at the rear of the nucleus by the mechanoresponsive recruitment of cytoplasmic linker-associated proteins, which dynamically strengthens and repairs the lattice. These reinforced microtubules form the mechanostat: an adaptive feedback mechanism that allows the cell to both withstand compressive force and spatiotemporally organize contractility signalling pathways. The microtubule mechanostat facilitates nuclear positioning and coordinates force production to enable the cell to pass through constrictions. Disruption of the mechanostat imbalances cortical contractility, stalling migration and ultimately resulting in catastrophic cell rupture. Our findings reveal a role for microtubules as cellular sensors that detect and respond to compressive forces, enabling movement and ensuring survival in mechanically demanding environments.
    DOI:  https://doi.org/10.1038/s41556-024-01476-x
  15. Heliyon. 2024 Aug 15. 10(15): e35721
    Glycolysis and chemoresistance in acute myeloid leukemia.
    Yan Yang, Jianlin Pu, You Yang.
      While traditional high-dose chemotherapy can effectively prolong the overall survival of acute myeloid leukemia (AML) patients and contribute to better prognostic outcomes, the advent of chemoresistance is a persistent challenge to effective AML management in the clinic. The therapeutic resistance is thought to emerge owing to the heterogeneous and adaptable nature of tumor cells when exposed to exogenous stimuli. Recent studies have focused on exploring metabolic changes that may afford novel opportunities to treat AML, with a particular focus on glycolytic metabolism. The Warburg effect, a hallmark of cancer, refers to metabolism of glucose through glycolysis under normoxic conditions, which contributes to the development of chemoresistance. Despite the key significance of this metabolic process in the context of malignant transformation, the underlying molecular mechanisms linking glycolysis to chemoresistance in AML remain incompletely understood. This review offers an overview of the current status of research focused on the relationship between glycolytic metabolism and AML resistance to chemotherapy, with a particular focus on the contributions of glucose transporters, key glycolytic enzymes, signaling pathways, non-coding RNAs, and the tumor microenvironment to this relationship. Together, this article will provide a foundation for the selection of novel therapeutic targets and the formulation of new approaches to treating AML.
    Keywords:  Acute myeloid leukemia; Chemoresistance; Glycolysis
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e35721
  16. Stem Cell Reports. 2024 Aug 06. pii: S2213-6711(24)00215-7. [Epub ahead of print]
    Efficient generation of human immune system rats using human CD34+ cells.
    Séverine Ménoret, Florence Renart-Depontieu, Gaelle Martin, Kader Thiam, Ignacio Anegon.
      Human immune system (HIS) mice generated using human CD34+ hematopoietic stem cells serve as a pivotal model for the in vivo evaluation of immunotherapies for humans. Yet, HIS mice possess certain limitations. Rats, due to their size and comprehensive immune system, hold promise for translational experiments. Here, we describe an efficacious method for long-term immune humanization, through intrahepatic injection of hCD34+ cells in newborn immunodeficient rats expressing human SIRPα. In contrast to HIS mice and similar to humans, HIS rats showed in blood a predominance of T cells, followed by B cells. Immune humanization was also high in central and secondary lymphoid organs. HIS rats treated with the anti-human CD3 antibody were depleted of human T cells, and human cytokines were detected in sera. We describe for the first time a method to efficiently generate HIS rats. HIS rats have the potential to be a useful model for translational immunology.
    Keywords:  cancer models; human immune system mice; immunodeficient rodents; immunotherapy; regenerative medicine; transplantation
    DOI:  https://doi.org/10.1016/j.stemcr.2024.07.005
  17. Pediatr Blood Cancer. 2024 Aug 16. e31286
    Venetoclax for pediatric patients with newly diagnosed acute myeloid leukemia.
    Amber Gibson, Samantha Dickson, David McCall, Miriam Garcia, Jeremy Connors, Jiasen He, Michael Roth, Cesar Nunez, Branko Cuglievan.
      This retrospective study at the University of Texas MD Anderson Cancer Center evaluated frontline venetoclax combination therapy in 11 pediatric/adolescent patients with acute myeloid leukemia (AML). Despite the small sample size and retrospective nature, the treatment demonstrated safety and potential efficacy, with most patients achieving early complete remission. Adverse events were consistent with other AML therapies, and no discontinuations due to toxicity occurred. While acknowledging study limitations, including selection bias and diverse concurrent therapies, this research underscores the promising role of venetoclax in pediatric AML. Further investigation is crucial to validate its long-term efficacy in this population.
    Keywords:  acute myeloid leukemia; pediatric; venetoclax
    DOI:  https://doi.org/10.1002/pbc.31286
  18. Cell Biochem Biophys. 2024 Aug 17.
    miR-149-3p Enhances Drug Sensitivity of AML Cells by Inhibiting Warburg Effect Through PI3K/AKT Pathway.
    Xi Chen, Yan Song, Yaoyao Tian, Xiushuai Dong, Yuying Chang, Wei Wang.
      Acute myeloid leukemia (AML) is a kind of heterogeneous hematologic malignancy with high incidence, which is usually treated by intensive and maintenance treatment with large dose of conventional chemotherapy drugs. However, cell resistance is still an unsolved problem. The abnormal expression of miRNAs is closely related to the pathogenesis and progression of AML, and affects the drug resistance of cancer cells. miR-149-3p plays an important role in the resistance of cancer cells to cisplatin, and plays an excellent anti-tumor activity. By studying the function of miR-149-3p, it is expected to find new therapeutic methods to reverse chemotherapy resistance. In order to explore the mechanism of action of miR-149-3p on AML chemotherapeutic drug sensitivity, we explored the relationship between the Warburg effect and AML chemotherapeutic drug resistance. Based on AML cells, transfection of miR-149-3p inhibitor/NC and Warburg effect inhibitor (2DG) and PI3K/AKT pathway inhibitor (LY294002) were used to investigate the mechanism of IFN-γ regulating chemotherapy resistance of AML cells through Warburg effect. Down-regulation of miR-149-3p significantly inhibited drug sensitivity of AML cells. Down-regulation of miR-149-3p significantly promoted proliferation and invasion of AML cells while inhibiting apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. Down-regulation of miR-149-3p significantly promoted the expression of Warburg effect-related proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and Glucose transporter 1 (GLUT1), glucose consumption, lactic acid, and intracellular ATP production. After inhibiting the Warburg effect with 2DG, the effect of miR-149-3p was inhibited, suggesting that upregulation of miR-149-3p reversed AML cell resistance by inhibiting the Warburg effect. In addition, miR-149-3p interacted with AKT1. Down-regulation of miR-149-3p increased the expression of inosine phosphate 3 kinase (PI3K), protein kinase B (AKT), and multi-drug resistance protein (MDR1). LY294002 inhibited the expression of these proteins, and down-regulation of miR-149-3p reversed the effect of LY294002 and improved the drug resistance of cells. Upregulation of miR-149-3p expression may potentially be a therapeutic target for AML resistance. It has been shown to inhibit PI3K/AKT pathway activation, thereby inhibiting the Warburg effect, and affecting cell proliferation, apoptosis, and drug resistance.
    Keywords:  Acute myeloid leukemia; Drug sensitivity; PI3K/AKT signaling pathway; Warburg effect; miR-149-3p
    DOI:  https://doi.org/10.1007/s12013-024-01412-8
  19. Int J Hematol. 2024 Aug 22.
    Recent advances in AML with mutated NPM1.
    Yuichi Ishikawa, Yoko Ushijima, Hitoshi Kiyoi.
      Nucleophosmin 1 (NPM1) mutation is one of the most prevalent genetic mutations in adult acute myeloid leukemia (AML) and is particularly predominant in AML with a normal karyotype. NPM1 is a chaperone protein that plays various roles in several cellular processes. Wild-type NPM1 is normally localized to the nucleus, whereas mutant NPM1 proteins exhibit altered cytoplasmic localization. Clinically, AML with mutated NPM1 without FLT3-ITD is associated with a higher complete remission rate and improved overall survival. AML with mutated NPM1 is categorized as a distinct genetic entity in the World Health Organization classification of hematopoietic malignancies due to its unique clinical and biological features. However, the precise roles of NPM1 in normal hematopoiesis and in AML development remain unclear. Recent studies have revealed various clinical applications of NPM1 mutations in AML treatment, particularly in measurable residual disease analyses that target mutant NPM1 transcripts and in potential therapeutic applications of menin inhibitors and XPO-1 inhibitors for AML with mutated NPM1. Thus, NPM1 mutation is highly significant in AML classification, prognosis, response assessment, and molecular targeted therapies. Here, we review recent progress in clinical and biological aspects of AML with mutated NPM1 including molecular targeted therapy.
    Keywords:   NPM1 mutation; AML; Molecular targeted therapy; Pathogenesis; Prognosis
    DOI:  https://doi.org/10.1007/s12185-024-03835-8
  20. Clin Exp Metastasis. 2024 Aug 20.
    Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics.
    Mohamed H Elbahoty, Bhavyasree Papineni, Rajeev S Samant.
      Multiple myeloma (MM) is a clinical disorder characterized by aberrant plasma cell growth in the bone marrow microenvironment. Globally, the prevalence of MM has been steadily increasing at an alarming rate. In the United States, more than 30,000 cases will be diagnosed in 2024 and it accounts for about 2% of cancer diagnoses and more than 2% of cancer deaths, more than double the worldwide figure. Both symptomatic and active MM are distinguished by uncontrolled plasma cell growth, which results in severe renal impairment, anemia, hypercalcemia, and bone loss. Multiple drugs have been approved by the FDA and are now widely used in clinical practice for MM. Although triplet and quadruplet induction regimens, autologous stem cell transplantation (ASCT), and maintenance treatment are used, MM continues to be an incurable illness characterized by relapses that may occur at various phases of its progression. MM patients with frailty, extramedullary disease, plasma cell leukemia, central nervous system recurrence, functional high risk, and the elderly are among those with the greatest current unmet needs. The high cost of care is an additional challenge. MM cells are highly protein secretary cells and thus are dependent on the activation of certain translation pathways. MM also has a high chance of altering ribosomal protein-encoding genes like MYC mutation. In this article we discuss the importance of ribosome biogenesis in promoting MM and RNA polymerase I inhibition as an upcoming treatment with potential promise for MM patients.
    Keywords:  Multiple myeloma; RNA polymerase I; Relapsed–refractory disease; Ribosome biogenesis; Treatment
    DOI:  https://doi.org/10.1007/s10585-024-10305-2
  21. iScience. 2024 Aug 16. 27(8): 110557
    Substrate stiffness alters layer architecture and biophysics of human induced pluripotent stem cells to modulate their differentiation potential.
    Jack Llewellyn, Anne Charrier, Rossana Cuciniello, Emmanuèle Helfer, Rosanna Dono.
      Lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs) relies on complex interactions between biochemical and physical cues. Here we investigated the ability of hiPSCs to undergo lineage commitment in response to inductive signals and assessed how this competence is modulated by substrate stiffness. We showed that Activin A-induced hiPSC differentiation into mesendoderm and its derivative, definitive endoderm, is enhanced on gel-based substrates softer than glass. This correlated with changes in tight junction formation and extensive cytoskeletal remodeling. Further, live imaging and biophysical studies suggested changes in cell motility and interfacial contacts underlie hiPSC layer reshaping on soft substrates. Finally, we repurposed an ultra-soft silicone gel, which may provide a suitable substrate for culturing hiPSCs at physiological stiffnesses. Our results provide mechanistic insight into how epithelial mechanics dictate the hiPSC response to chemical signals and provide a tool for their efficient differentiation in emerging stem cell therapies.
    Keywords:  Biophysics; Mechanobiology; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2024.110557
  22. J Cell Biol. 2024 Nov 04. pii: e202401091. [Epub ahead of print]223(11):
    Coordination of force-generating actin-based modules stabilizes and remodels membranes in vivo.
    Marco Heydecker, Akiko Shitara, Desu Chen, Duy T Tran, Andrius Masedunskas, Muhibullah S Tora, Seham Ebrahim, Mark A Appaduray, Jorge Luis Galeano Niño, Abhishek Bhardwaj, Kedar Narayan, Edna C Hardeman, Peter W Gunning, Roberto Weigert.
      Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes.
    DOI:  https://doi.org/10.1083/jcb.202401091
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