bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–05–26
twenty-one papers selected by
William Grey, University of York
  1. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
  2. Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation.
  3. Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
  4. Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML.
  5. Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia.
  6. Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging.
  7. Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.
  8. Influence of donor-recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation.
  9. Heart failure promotes multimorbidity through innate immune memory.
  10. IL-1 in Aging and Pathologies of Hematopoietic Stem Cells.
  11. FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.
  12. A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
  13. Establishment of reference values based on influential characteristics of hematopoietic stem cells and immune cell subsets in the bone marrow.
  14. The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence.
  15. NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
  16. CD8+ T-cell Differentiation and Dysfunction Inform Treatment Response in Acute Myeloid Leukemia.
  17. A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML.
  18. Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia.
  19. Ligand binding initiates single-molecule integrin conformational activation.
  20. ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.
  21. Tweaking the NRF2 signaling cascade in human myelogenous leukemia cells by artificial nano-organelles.
  1. Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]
    SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
    Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.
      Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
    Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin
    DOI:  https://doi.org/10.1016/j.stem.2024.04.023
  2. Stem Cell Res Ther. 2024 May 20. 15(1): 145
    Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation.
    Hyun Sung Park, Byung-Chul Lee, Dong-Hoon Chae, Aaron Yu, Jae Han Park, Jiyoung Heo, Myoung Hee Han, Keonwoo Cho, Joong Won Lee, Ji-Won Jung, Cynthia E Dunbar, Mi-Kyung Oh, Kyung-Rok Yu.
       BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated.
    METHODS: In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs.
    RESULTS: Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs.
    CONCLUSION: In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.
    Keywords:  Bone marrow niche; Cigarette smoking extract; Mesenchymal stem cells; NLRP3; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s13287-024-03731-2
  3. Nat Commun. 2024 May 21. 15(1): 4325
    Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
    Giulia Schiroli, Vinay Kartha, Fabiana M Duarte, Trine A Kristiansen, Christina Mayerhofer, Rojesh Shrestha, Andrew Earl, Yan Hu, Tristan Tay, Catherine Rhee, Jason D Buenrostro, David T Scadden.
      Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-48508-6
  4. iScience. 2024 Jun 21. 27(6): 109809
    Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML.
    Laura Barreyro, Avery M Sampson, Kathleen Hueneman, Kwangmin Choi, Susanne Christie, Vighnesh Ramesh, Michael Wyder, Dehua Wang, Mario Pujato, Kenneth D Greis, Gang Huang, Daniel T Starczynowski.
      Dysregulated innate immune signaling is linked to preleukemic conditions and myeloid malignancies. However, it is unknown whether sustained innate immune signaling contributes to malignant transformation. Here we show that cell-intrinsic innate immune signaling driven by miR-146a deletion (miR-146aKO), a commonly deleted gene in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), cooperates with mutant RUNX1 (RUNX1mut) to initially induce marrow failure and features of MDS. However, miR-146aKO hematopoietic stem and/or progenitor cells (HSPCs) expressing RUNX1mut eventually progress to a fatal AML. miR-146aKO HSPCs exhaust during serial transplantation, while expression of RUNX1mut restored their hematopoietic cell function. Thus, HSPCs exhibiting dysregulated innate immune signaling require a second hit to develop AML. Inhibiting the dysregulated innate immune pathways with a TRAF6-UBE2N inhibitor suppressed leukemic miR-146aKO/RUNX1mut HSPCs, highlighting the necessity of TRAF6-dependent cell-intrinsic innate immune signaling in initiating and maintaining AML. These findings underscore the critical role of dysregulated cell-intrinsic innate immune signaling in driving preleukemic cells toward AML progression.
    Keywords:  Disease; Immune response; Pathophysiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109809
  5. Cell Rep Med. 2024 May 15. pii: S2666-3791(24)00277-5. [Epub ahead of print] 101585
    Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia.
    Guillermo Montalban-Bravo, Natthakan Thongon, Juan Jose Rodriguez-Sevilla, Feiyang Ma, Irene Ganan-Gomez, Hui Yang, Yi June Kim, Vera Adema, Bethany Wildeman, Tomoyuki Tanaka, Faezeh Darbaniyan, Gheath Al-Atrash, Karen Dwyer, Sanam Loghavi, Rashmi Kanagal-Shamanna, Xingzhi Song, Jianhua Zhang, Koichi Takahashi, Hagop Kantarjian, Guillermo Garcia-Manero, Simona Colla.
      RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.
    Keywords:  CMML; MCL1; NF-kB; RAS; multiomics; progression; transcriptomics
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101585
  6. Curr Osteoporos Rep. 2024 May 23.
    Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging.
    Emily R Quarato, Noah A Salama, Laura M Calvi.
       PURPOSE OF THE REVIEW: In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease.
    RECENT FINDINGS: Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.
    Keywords:   Bone Marrow Stromal Cells; Aging; Hematopoietic stem cells; Mitochondria; Osteoimmunology
    DOI:  https://doi.org/10.1007/s11914-024-00874-2
  7. Cancer Discov. 2024 May 24.
    Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.
    Anagha Inguva Sheth, Mark J Althoff, Hunter Tolison, Krysta Engel, Maria L Amaya, Anna E Krug, Tracy N Young, Mohammad Minhajuddin, Shanshan Pei, Sweta B Patel, Amanda Winters, Regan Miller, Ian T Shelton, Jonathan St-Germain, Tianyi Ling, Courtney L Jones, Brian Raught, Austin E Gillen, Monica Ransom, Sarah Staggs, Clayton A Smith, Daniel A Pollyea, Brett M Stevens, Craig T Jordan.
      Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1145
  8. Hemasphere. 2024 May;8(5): e80
    Influence of donor-recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation.
    Syed A Mian, Linda Ariza-McNaughton, Fernando Anjos-Afonso, Remisha Guring, Sophie Jackson, Aytug Kizilors, John Gribben, Dominique Bonnet.
      Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor-recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex-specific engraftment levels with significant differences observed in the lineage output of normal CD34+ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre-clinical research.
    DOI:  https://doi.org/10.1002/hem3.80
  9. Sci Immunol. 2024 May 24. 9(95): eade3814
    Heart failure promotes multimorbidity through innate immune memory.
    Yukiteru Nakayama, Katsuhito Fujiu, Tsukasa Oshima, Jun Matsuda, Junichi Sugita, Takumi James Matsubara, Yuxiang Liu, Kohsaku Goto, Kunihiro Kani, Ryoko Uchida, Norifumi Takeda, Hiroyuki Morita, Yingda Xiao, Michiko Hayashi, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Soh Ishiguro, Yusuke Kijima, Nozomu Yachie, Satoshi Yamazaki, Ryo Yamamoto, Fujimi Kudo, Mio Nakanishi, Atsushi Iwama, Ryoji Fujiki, Atsushi Kaneda, Osamu Ohara, Ryozo Nagai, Ichiro Manabe, Issei Komuro.
      Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."
    DOI:  https://doi.org/10.1126/sciimmunol.ade3814
  10. Blood. 2024 May 23. pii: blood.2023023105. [Epub ahead of print]
    IL-1 in Aging and Pathologies of Hematopoietic Stem Cells.
    Markus Gabriel Manz, Francisco Caiado.
      Defense-oriented inflammatory reactivity supports survival at younger age, but might contribute to health impairments in modern, aging societies. The IL-1 cytokines are highly conserved and regulated, pleiotropic mediators of inflammation, essential to respond adequately to infection and tissue damage, but also with potential host damaging effects when left unresolved. In this review, we discuss how continuous low-level IL-1 signaling contributes to aging-associated hematopoietic stem and progenitor cell (HSPC) functional impairments and how this inflammatory selective pressure acts as a driver of more profound hematological alterations, such as clonal hematopoiesis of indeterminate potential (CHIP), and to overt HSPC diseases, like myeloproliferative and myelodysplastic neoplasia as well as acute myeloid leukemia. Based on this, we outline how IL-1 pathway inhibition might be utilized to prevent or treat "inflamm-aging" associated HSPC pathologies.
    DOI:  https://doi.org/10.1182/blood.2023023105
  11. Hematol Oncol. 2024 May;42(3): e3281
    FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.
    María Turos-Cabal, Ana M Sánchez-Sánchez, Noelia Puente-Moncada, Federico Herrera, Isaac Antolin, Carmen Rodríguez, Vanesa Martín.
      The FLT3-ITD mutation represents the most frequent genetic alteration in newly diagnosed acute myeloid leukemia (AML) patient and is associated with poor prognosis. Mutation result in the retention of a constitutively active form of this receptor in the endoplasmic reticulum (ER) and the subsequent modification of its downstream effectors. Here, we assessed the impact of such retention on ER homeostasis and found that mutant cells present lower levels of ER stress due to the overexpression of ERO1α, one of the main proteins of the protein folding machinery at the ER. Overexpression of ERO1α resulted essential for ITD mutant cells survival and chemoresistance and also played a crucial role in shaping the type of glucose metabolism in AML cells, being the mitochondrial pathway the predominant one in those with a higher ER stress (non-mutated cells) and the glycolytic pathway the predominant one in those with lower ER stress (mutated cells). Our data indicate that FLT3 mutational status dictates the route for glucose metabolism in an ERO1α depending on manner and this provides a survival advantage to tumors carrying these ITD mutations.
    Keywords:  ERO1α; FLT3; acute myeloid leukemia; endoplasmic reticulum; glucose metabolism; mitochondria associated membranes
    DOI:  https://doi.org/10.1002/hon.3281
  12. bioRxiv. 2024 May 10. pii: 2024.05.07.592983. [Epub ahead of print]
    A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
    Asiri Ediriwickrema, Yusuke Nakauchi, Amy C Fan, Thomas Köhnke, Xiaoyi Hu, Bogdan A Luca, YeEun Kim, Sreejith Ramakrishnan, Margaret Nakamoto, Daiki Karigane, Miles H Linde, Armon Azizi, Aaron M Newman, Andrew J Gentles, Ravindra Majeti.
      Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of the human body. Human MPPs remain ill-defined whereas mouse MPPs have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single cell analyses and complementary functional assays, we identified new human MPPs and oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow with distinct biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We show that within the canonical Lin-CD34+CD38dim/loCD90CD45RA-MPP population, there is a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69-erythroid-biased MPP. We also show that the canonical Lin-CD34+CD38dim/loCD90-CD45RA+ LMPP population can be separated into a CD2+ LMPP with lymphoid and myeloid potential, a CD2-LMPP with high lymphoid potential, and a CLL1+ GMP with minimal lymphoid potential. We used these new HSPC profiles to study human and mouse bone marrow cells and observe limited cell type specific homology between humans and mice and cell type specific changes associated with aging. By identifying and functionally characterizing new adult MPP sub-populations, we provide an updated reference and framework for future studies in human hematopoiesis.
    DOI:  https://doi.org/10.1101/2024.05.07.592983
  13. Heliyon. 2024 May 15. 10(9): e30888
    Establishment of reference values based on influential characteristics of hematopoietic stem cells and immune cell subsets in the bone marrow.
    Rebar N Mohammed, Najmaddin S H Khoshnaw, Vian Faeq Mohammed, Dastan O Hassan, Chra Nawfal Abdullah, Tavan Ismael Mahmood, Huda A Abbass, Dereen Ahmed, Kani D Noori, Lanja I Saeed, Salah Mohammed Salih, Hiwa S Sidiq, Dlnya Omer Ali, Alan Shwan, Ignazio Majolino, Francesco Ipsevich.
      Hematopoietic stem cell transplantation is still a curative treatment for many haematological cancers. Many factors, such as age, sex, ethnic background, smoking status, and body mass index, affect average reference values in different populations. This study aimed to establish a reference range for the absolute numbers and percentages of healthy individuals' hematopoietic stem cells and immune cells in the bone marrow. Seventy-one healthy donors (32 males and 39 females) were enrolled in the study. Following bone marrow harvesting, using flow cytometry, immunophenotyping was performed to determine the absolute number and percentage of CD34+ stem cells and various immune subsets. We found no statistically significant difference in the absolute count of HSCs or immune cell subsets in the bone marrow between males and females. Regarding age, the younger group had more significant CD34+ and immune cell subsets. Donors with healthier body weights tend to have richer bone marrow cellularity. Establishing a reference value for hematopoietic stem cells and immune cells in the bone marrow based on various influential factors is pivotal for defining bone marrow status and donor selection.
    Keywords:  Bone marrow graft; HSC; Healthy donor; Immune cells; Reference range
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30888
  14. Biochim Biophys Acta Rev Cancer. 2024 May 16. pii: S0304-419X(24)00050-7. [Epub ahead of print]1879(4): 189119
    The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence.
    Bashar A Alhasan, Alexey V Morozov, Irina V Guzhova, Boris A Margulis.
      Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.
    Keywords:  DUBs; Dormancy; E3 ligases; Proteasomes; Reawakening; Tumor recurrence; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189119
  15. J Cell Biol. 2024 Sep 02. pii: e202402006. [Epub ahead of print]223(9):
    NEKL-4 regulates microtubule stability and mitochondrial health in ciliated neurons.
    Kaiden M Power, Ken C Nguyen, Andriele Silva, Shaneen Singh, David H Hall, Christopher Rongo, Maureen M Barr.
      Ciliopathies are often caused by defects in the ciliary microtubule core. Glutamylation is abundant in cilia, and its dysregulation may contribute to ciliopathies and neurodegeneration. Mutation of the deglutamylase CCP1 causes infantile-onset neurodegeneration. In C. elegans, ccpp-1 loss causes age-related ciliary degradation that is suppressed by a mutation in the conserved NEK10 homolog nekl-4. NEKL-4 is absent from cilia, yet it negatively regulates ciliary stability via an unknown, glutamylation-independent mechanism. We show that NEKL-4 was mitochondria-associated. Additionally, nekl-4 mutants had longer mitochondria, a higher baseline mitochondrial oxidation state, and suppressed ccpp-1∆ mutant lifespan extension in response to oxidative stress. A kinase-dead nekl-4(KD) mutant ectopically localized to ccpp-1∆ cilia and rescued degenerating microtubule doublet B-tubules. A nondegradable nekl-4(PEST∆) mutant resembled the ccpp-1∆ mutant with dye-filling defects and B-tubule breaks. The nekl-4(PEST∆) Dyf phenotype was suppressed by mutation in the depolymerizing kinesin-8 KLP-13/KIF19A. We conclude that NEKL-4 influences ciliary stability by activating ciliary kinesins and promoting mitochondrial homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202402006
  16. Blood. 2024 May 22. pii: blood.2023021680. [Epub ahead of print]
    CD8+ T-cell Differentiation and Dysfunction Inform Treatment Response in Acute Myeloid Leukemia.
    Francesco Mazziotta, Luca Biavati, Joseph Cataquiz Rimando, Sergio Rutella, Nicholas Borcherding, Sonali Parbhoo, Rupkatha Mukhopadhyay, Hanna A Knaus, Peter Valent, Hubert Hackl, Ivan Borrello, Bruce R Blazar, Katerina Hatzi, Ivana Gojo, Leo Luznik.
      The interplay between T-cell states of differentiation, dysfunction, and treatment response in acute myeloid leukemia (AML) remains unclear. Here, we leveraged a multimodal approach encompassing high-dimensional flow cytometry and single-cell transcriptomics and found that early memory CD8+ T cells are associated with therapy response and exhibit a bifurcation into two distinct terminal end states. One state is enriched for markers of activation, whereas the other expresses NK-like and senescence markers. The skewed clonal differentiation trajectory towards CD8+ senescence was also a hallmark indicative of therapy resistance. We validated these findings by generating an AML CD8+ single-cell atlas integrating our data and other independent datasets. Finally, our analysis revealed that an imbalance between CD8+ early memory and senescent-like cells is linked to AML treatment refractoriness and poor survival. Our study provides crucial insights into the dynamics of CD8+ T-cell differentiation and advances our understanding of CD8+ T-cell dysfunction in AML.
    DOI:  https://doi.org/10.1182/blood.2023021680
  17. NPJ Precis Oncol. 2024 May 18. 8(1): 105
    A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML.
    E Onur Karakaslar, Jeppe F Severens, Elena Sánchez-López, Peter A van Veelen, Mihaela Zlei, Jacques J M van Dongen, Annemarie M Otte, Constantijn J M Halkes, Peter van Balen, Hendrik Veelken, Marcel J T Reinders, Marieke Griffioen, Erik B van den Akker.
      The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.
    DOI:  https://doi.org/10.1038/s41698-024-00596-9
  18. Leuk Lymphoma. 2024 May 22. 1-11
    Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia.
    Karolina Bełdzińska-Gądek, Ewa Zarzycka, Krzysztof Pastuszak, Katarzyna Borman, Krzysztof Lewandowski, Jan M Zaucha, Witold Prejzner.
      Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A-rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.
    Keywords:  Lineage switch; acute leukemia; immunotherapy
    DOI:  https://doi.org/10.1080/10428194.2024.2351194
  19. Cell. 2024 May 14. pii: S0092-8674(24)00475-6. [Epub ahead of print]
    Ligand binding initiates single-molecule integrin conformational activation.
    Jing Li, Myung Hyun Jo, Jiabin Yan, Taylor Hall, Joon Lee, Uriel López-Sánchez, Sophia Yan, Taekjip Ha, Timothy A Springer.
      Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin β-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.
    Keywords:  FRET; inside-out signaling; integrin activation pathway; integrin conformational changes; integrin conformational dynamics; ligand; outside-in signaling; single molecule; talin
    DOI:  https://doi.org/10.1016/j.cell.2024.04.049
  20. Autophagy. 2024 May 18. 1-17
    ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.
    Zhangyang Qi, Weiqi Yang, Baibing Xue, Tingjun Chen, Xianjie Lu, Rong Zhang, Zhichao Li, Xiaoqing Zhao, Yang Zhang, Fabin Han, Xiaohong Kong, Ruikang Liu, Xue Yao, Rui Jia, Shiqing Feng.
      Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.
    Keywords:  Autophagy; ROS; bleomycin; cellular senescence; lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1080/15548627.2024.2353548
  21. Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2219470121
    Tweaking the NRF2 signaling cascade in human myelogenous leukemia cells by artificial nano-organelles.
    Konstantin M P Wolf, Viviana Maffeis, Cora-Ann Schoenenberger, Tamara Zünd, Liron Bar-Peled, Cornelia G Palivan, Viola Vogel.
      NRF2 (nuclear factor erythroid-2-related factor 2) is a key regulator of genes involved in the cell's protective response to oxidative stress. Upon activation by disturbed redox homeostasis, NRF2 promotes the expression of metabolic enzymes to eliminate reactive oxygen species (ROS). Cell internalization of peroxisome-like artificial organelles that harbor redox-regulating enzymes was previously shown to reduce ROS-induced stress and thus cell death. However, if and to which extent ROS degradation by such nanocompartments interferes with redox signaling pathways is largely unknown. Here, we advance the design of H2O2-degrading artificial nano-organelles (AnOs) that exposed surface-attached cell penetrating peptides (CPP) for enhanced uptake and were equipped with a fluorescent moiety for rapid visualization within cells. To investigate how such AnOs integrate in cellular redox signaling, we engineered leukemic K562 cells that report on NRF2 activation by increased mCherry expression. Once internalized, ROS-metabolizing AnOs dampen intracellular NRF2 signaling upon oxidative injury by degrading H2O2. Moreover, intracellular AnOs conferred protection against ROSinduced cell death in conditions when endogenous ROS-protection mechanisms have been compromised by depletion of glutathione or knockdown of NRF2. We demonstrate CPP-facilitated AnO uptake and AnO-mediated protection against ROS insults also in the T lymphocyte population of primary peripheral blood mononuclear cells from healthy donors. Overall, our data suggest that intracellular AnOs alleviated cellular stress by the on-site reduction of ROS.
    Keywords:  NRF2 signaling; ROS scavenging; antioxidant defense; polymersomes; reactive oxygen species
    DOI:  https://doi.org/10.1073/pnas.2219470121
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