bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–06–29
seventeen papers selected by
William Grey, University of York
  1. The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
  2. Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
  3. JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects.
  4. Quantification of intrinsic regulatory factors refines human hematopoietic progenitor definitions and reveals early erythroid lineage priming.
  5. Vascular endothelial growth factor-induced vascular permeability results in drastic and reversible hematopoietic stem cell mobilization.
  6. The TET protein family interactor PROSER1 sustains hematopoietic stem cell function.
  7. Deciphering MARCH5's impact on multiple myeloma: insights into autophagy regulation and AKT-FOXO3 signaling.
  8. There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.
  9. A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.
  10. Mechanism of umbilical cord mesenchymal stem cells in the expansion of umbilical cord blood-derived hematopoietic stem cells in vitro.
  11. Hallmarks of stem cell aging.
  12. Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.
  13. Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells.
  14. Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.
  15. Ambroxol induces myeloma cell death by inhibiting autophagy.
  16. Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer.
  17. BAG2 releases SAMD4B upon sensing of arginine deficiency to promote tumor cell survival.
  1. J Clin Invest. 2025 Jun 26. pii: e180913. [Epub ahead of print]
    The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
    Siera A Tomishima, Dale D Kim, Nadia Porter, Ipsita Guha, Asif A Dar, Yohaniz Ortega-Burgos, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Christopher S Thom, Robert L Bowman, Paula M Oliver.
      The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.
    Keywords:  Bone marrow differentiation; Hematology; Hematopoietic stem cells; Immunology; Stem cells; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI180913
  2. Blood. 2025 Jun 25. pii: blood.2024026113. [Epub ahead of print]
    Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
    Aristi Damaskou, Rachael Wilson, Malgorzata Gozdecka, George Giotopoulos, Ryan Asby, Maria Eleftheriou, Muxin Gu, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, Ambrine Sahal, Binje Vick, Evangelia K Papachristou, Ashley Sawle, Eliza Yankova, Monika Dudek, Xiaoxuan Liu, James Russell, Justyna Rak, Christine Hilcenko, Clive S D'Santos, Irmela Jeremias, Jean-Emmanuel Sarry, Konstantinos Tzelepis, Brian Jp Huntly, Alan J Warren, Omid Tavana, George S Vassiliou.
      NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis amongst its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examine the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knock-in Npm1cA/+ mice. We discover that many proteins involved in ribosome biogenesis are significantly depleted in these murine HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that pre-leukemic Npm1cA/+ HSPCs display higher sensitivity to RNA polymerase I inhibitors, including Actinomycin D (ActD), compared to Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells, whilst low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR dropout screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models. Our findings propose that targeted disruption of ribosome biogenesis should be explored as a therapeutic strategy against NPM1-mutant AML.
    DOI:  https://doi.org/10.1182/blood.2024026113
  3. EMBO Rep. 2025 Jun 25.
    JMJD3-mediated senescence is required to overcome stress-induced hematopoietic defects.
    Yuichiro Nakata, Takeshi Ueda, Yasuyuki Sera, Miho Koizumi, Katsutoshi Imamura, Akinori Kanai, Ken-Ichiro Ikeda, Norimasa Yamasaki, Akiko Nagamachi, Kohei Kobatake, Masataka Taguchi, Yusuke Sotomaru, Tatsuo Ichinohe, Zen-Ichiro Honda, Takuro Nakamura, Ichiro Manabe, Toshio Suda, Keiyo Takubo, Osamu Kaminuma, Hiroaki Honda.
      Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence by upregulating p16Ink4a in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. Jmjd3 deficiency does not alter global H3K27me3 levels, indicating that JMJD3 epigenetically regulates specific and limited JMJD3 targets under stress. JMJD3 deficiency also impairs stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress. These impaired phenotypes are rescued through exogenous and retroviral introduction of p16Ink4a. This JMJD3-p16INK4a axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a selective JMJD3 inhibitor attenuates leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress.
    Keywords:  Cellular senescence; Hematopoietic stem cell; Histone demethylase; Stress hematopoiesis
    DOI:  https://doi.org/10.1038/s44319-025-00502-9
  4. Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00684-9. [Epub ahead of print]44(7): 115913
    Quantification of intrinsic regulatory factors refines human hematopoietic progenitor definitions and reveals early erythroid lineage priming.
    Patricia Favaro, David R Glass, Luciene Borges, Reema Baskar, Avery Lam, Warren Reynolds, Daniel Ho, Trevor Bruce, Dmitry Tebaykin, Thomas Koehnke, Vanessa M Scanlon, Ilya Shestopalov, Sean C Bendall.
      Hematopoietic stem and progenitor cell (HSPC) transplantation is an essential therapy for hematological conditions, but finer definitions of human HSPC subsets with associated function could enable better tuning of grafts and more routine, lower-risk application. To deeply phenotype HSPCs, following a screen of 328 antigens, we quantified 41 surface proteins and functional regulators on millions of CD34+ and CD34- cells, spanning four primary hematopoietic tissues: bone marrow, mobilized peripheral blood, cord blood, and fetal liver. We propose more granular definitions of HSPC subsets and present detailed differentiation trajectories of erythroid and myeloid lineages. These aspects of our revised human hematopoietic model are validated with corresponding epigenetic analysis, in vitro clonal differentiation assays, and an in vivo cell tracing model. Overall, we demonstrate the utility of using molecular regulators as surrogates for cellular identity and functional potential, providing a framework for description, prospective isolation, and cross-tissue comparison of HSPCs in humans.
    Keywords:  ATAC-sequencing; CP: Developmental biology; erythrocyte/megakaryocyte lineage; hematopoietic stem and progenitor cell; human hematopoiesis; in vivo lineage tracing; mass cytometry; molecular regulator; single cell; trajectory analysis; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115913
  5. Stem Cell Reports. 2025 Jun 17. pii: S2213-6711(25)00151-1. [Epub ahead of print] 102547
    Vascular endothelial growth factor-induced vascular permeability results in drastic and reversible hematopoietic stem cell mobilization.
    Stephanie Smith-Berdan, Mark Landon, Bryan Petkus, Leah Kramer, Alyssa Bercasio, Tuan Vo, Tobin Berger-Cahn, E Camilla Forsberg.
      Lifelong hematopoiesis as well as hematopoietic transplantation therapies is dependent on the ability of hematopoietic stem cells (HSCs) to effectively traffic across the bone marrow (BM) endothelium. Mounting evidence suggests that modulators of vascular permeability are potent regulators of HSC location. Here, we utilized a doxycycline-inducible mouse model to overexpress vascular endothelial growth factor A (VEGF-A) to alter vascular permeability. Remarkably, VEGF-induced permeability led to unprecedented HSC mobilization. HSC mobilization from the BM to the blood stream was rapid and reversible and required no additional drugs or manipulation. The mobilized HSCs were functional, as demonstrated by high levels of long-term multi-lineage reconstitution by VEGF-mobilized cells of irradiated recipients. Importantly, VEGF-induced permeability did not irrevocably destroy vascular BM niches, as transplantation experiments revealed improved long-term donor HSC engraftment in VEGF-overexpressing recipients. Collectively, these findings enhance our ability to regulate HSC trafficking to and from the BM and provide insight into improving the efficacy and safety of HSC mobilization and hematopoietic transplantation therapies.
    Keywords:  HSC engraftment; HSC mobilization; HSC trafficking; VEGF; bone marrow endothelium; hematopoietic stem cells; hematopoietic transplantation therapies; mouse model; transplantation; vascular endothelial growth factor; vascular niches; vascular permeability
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102547
  6. Blood Adv. 2025 Jun 24. pii: bloodadvances.2024015683. [Epub ahead of print]
    The TET protein family interactor PROSER1 sustains hematopoietic stem cell function.
    Elena V Knatko, Anna Fleming, Xiang Li, Phoebe Crawley, Ieva Budriunaite, Kasper D Rasmussen.
      Ten-Eleven-Translocation (TET) enzymes are epigenetic regulators important for prevention of hematological malignancies. PROSER1, a known TET protein interactor, has a critical role in modulating TET-mediated DNA demethylation during development. However, the potential involvement of PROSER1 in regulation of hematopoiesis and leukemogenesis remains unknown. Here, we demonstrate that the leukemia suppressive functions of TET2 are preserved in the absence of PROSER1. Nonetheless, we find that loss of PROSER1 partially recapitulates the aberrant enhancer DNA methylation phenotype observed upon TET2 knockout, suggesting that PROSER1 and TET2 play both cooperative and distinct roles in the regulation of DNA methylation in hematopoiesis. Importantly, using serial hematopoietic stem cell (HSC) transplantation assays, we find progressive exhaustion of HSC activity and reduction in hematopoietic lineage output upon loss of PROSER1. Our findings imply that, beyond the established role of TET2 loss-of-function mutations in promoting HSC expansion and leukemic transformation, accurate TET activity, regulated by PROSER1, is equally important to prevent HSC exhaustion and sustain normal hematopoiesis.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015683
  7. Blood Neoplasia. 2024 Dec;1(4): 100046
    Deciphering MARCH5's impact on multiple myeloma: insights into autophagy regulation and AKT-FOXO3 signaling.
    Hamed Bashiri, Ahad Khalilnezhad, Haruhito Totani, Joe Yeong, Tae-Hoon Chung, Felicia Wee, Yuezhen Xue, Zhen Wei Neo, Li Yen Chong, Wee Joo Chng, Atsushi Watanabe, Siok-Bian Ng, The Phyu, Toshio Suda.
      Multiple myeloma (MM) stands as a formidable blood malignancy, necessitating innovative therapeutic approaches. Excessive immunoglobulin production within myeloma cells leads to a buildup of toxic proteins, and autophagy plays a crucial role in their survival by degrading toxic aggregates and generating energy. Membrane-associated RING finger protein 5 (MARCH5) is an E3-ligase positioned at the outer mitochondrial membrane and has been shown to regulate autophagy by competing for MicroRNA 30a (MIR30A). Given the fundamental significance of autophagy in promoting the survival of myeloma cells, coupled with the regulatory role of MARCH5 in autophagic activity, we hypothesized that MARCH5 plays an essential function in MM and holds a pivotal position in the pathogenesis and progression of MM. We identified MARCH5's unique dependencies in MM cells by analyzing the Cancer Dependency Map, thereby establishing its significance in MM biology. Examining various data sets, including CoMMpass (Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile Study) and HOVON (Haemato-Oncology Foundation for Adults in the Netherlands), demonstrated a correlation between MARCH5 expression and patient outcomes. Knockdown of MARCH5 revealed a substantial reduction in MM cell viability, which was associated with a decrease in autophagic activity. Mechanistically, we unraveled a novel MARCH5/AKT/FOXO3 axis, wherein MARCH5 regulates autophagy through the Protein Kinase B (AKT)-mediated degradation of Forkhead Box O3 (FOXO3). Compromised MM cell viability observed with MARCH5 knockdown was recapitulated in FOXO3 knockdown experiments, validating the pivotal role of FOXO3 in mediating MARCH5's effects. In conclusion, this research highlights the crucial role of MARCH5 in MM, and the identified MARCH5/AKT/FOXO3 axis enhances our understanding of MM biology and provides a foundation for developing targeted therapies.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100046
  8. Hematol Transfus Cell Ther. 2025 Jun 18. pii: S2531-1379(25)00127-0. [Epub ahead of print]47(3): 103859
    There is no transfer of mitochondria from donor hematopoietic cells to recipient mesenchymal stromal cells after allogeneic hematopoietic stem cells transplantation in humans.
    Natalya Sats, Vadim Surin, Tatiana Abramova, Aleksandra Sadovskaya, Nataliya Petinati, Nikolay Kapranov, Ksenia Nikiforova, Nina Drize, Luisa Karaseva, Olga Pokrovskaya, Larisa Kuzmina, Elena Parovichnikova.
       INTRODUCTION: Multipotent mesenchymal stromal cells are progenitors of the bone marrow stromal microenvironment that support hematopoiesis. Mitochondria, which can be transferred between cells via nanotubes or extracellular vesicles, play a key role in the functions of mesenchymal stromal cells. In a murine model, donor hematopoietic stem and progenitor cells transfer functional mitochondria to bone marrow mesenchymal stromal cells of the recipient. The aim of this study was to find out whether such transfer occurs in humans after allogeneic hematopoietic stem cell transplantation.
    METHODS: This study included nine patients with acute leukemia who received a reduced intensity conditioning regimen. Donor hematopoietic stem and progenitor cells mobilized into peripheral blood were the source of transplanted stem cells. Total DNA was isolated from bone marrow mesenchymal stromal cells of each patient before and after transplantation and their respective donors' leukocytes. A fragment of mitochondrial DNA including the full-length control region was sequenced. The mitochondrial DNA sequence of each patient's mesenchymal stromal cells was compared before and after the procedure and with the respective donor leukocytes.
    RESULTS: Donor mitochondrial DNA was not detected in the mesenchymal stromal cells of any patient after transplantation even as trace amounts. Co-culturing donor leukocytes with intact and irradiated mesenchymal stromal cells in vitro did not lead to detection of donor mitochondrial DNA transfer.
    CONCLUSION: The data show that there is no mitochondrial transfer from donor hematopoietic stem and progenitor cells to recipient mesenchymal stromal cells after transplantation. Thus, the results indicate that one cannot count on improved mesenchymal stromal cell metabolism due to mitochondrial transfer. It is necessary to look for other ways to restore the stromal microenvironment.
    Keywords:  Hematopoietic stem cell transplantation; Mesenchymal stromal cells; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.htct.2025.103859
  9. Nat Med. 2025 Jun 27.
    A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.
    N Furer, N Rappoport, O Milman, S Tavor, A Lifshitz, A Bercovich, O Ben-Kiki, A Danin, M Kedmi, Z Shipony, D Lipson, E Meiri, G Yanai, S Shapira, N Arber, S Berdichevsky, J Tyner, S Joshi, D Landau, S Ganesan, N Dusaj, P Chamely, N Kaushansky, N Chapal-Ilani, R Shamir, A Tanay, L Shlush.
      With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven't been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.
    DOI:  https://doi.org/10.1038/s41591-025-03716-5
  10. J Int Med Res. 2025 Jun;53(6): 3000605251350968
    Mechanism of umbilical cord mesenchymal stem cells in the expansion of umbilical cord blood-derived hematopoietic stem cells in vitro.
    Zhuo-Yang Bian, Li Xu.
      The methodologies and applications of ex vivo expansion of umbilical cord blood cells represent a significant research domain, primarily owing to the distinctive characteristics of these cells and their prospective uses in regenerative medicine and hematopoietic stem cell transplantation. We searched PubMed and Web of Science using the terms "umbilical cord blood cells," "cytokine," "haematopoietic cells," "umbilical cord mesenchymal stem cells," "in vitro expansion," and "microenvironment," and the selected literature was organized and analyzed. We present a narrative review of the mechanisms by which umbilical cord mesenchymal stem cells enhance the in vitro expansion of umbilical cord blood-derived hematopoietic stem cells, focusing on three primary aspects: secretion of diverse cytokines to replicate the natural hematopoietic microenvironment, transmission of critical signals via direct cell-to-cell contact, and exertion of immunomodulatory effects to alleviate environmental stress. Although these processes can significantly promote the proliferation and survival of hematopoietic stem cells, the challenge of concurrently preserving the long-term stemness of these cells in an in vitro environment remains a critical issue for future research.
    Keywords:  Umbilical cord blood cells; cytokine; hematopoietic stem cells; in vitro expansion; microenvironment; umbilical cord mesenchymal stem cells
    DOI:  https://doi.org/10.1177/03000605251350968
  11. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  12. Nat Cancer. 2025 Jun 27.
    Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.
    Ilaria Iacobucci, Andy G X Zeng, Qingsong Gao, Laura Garcia-Prat, Pradyumna Baviskar, Sayyam Shah, Alex Murison, Veronique Voisin, Michelle Chan-Seng-Yue, Cheng Cheng, Chunxu Qu, Colin Bailey, Matthew Lear, Matthew T Witkowski, Xin Zhou, Airen Zaldivar Peraza, Karishma Gangwani, Anjali S Advani, Selina M Luger, Mark R Litzow, Jacob M Rowe, Elisabeth M Paietta, Wendy Stock, John E Dick, Charles G Mullighan.
      Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR::ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a 'multipotency score' most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-025-00987-2
  13. Blood Neoplasia. 2024 Dec;1(4): 100052
    Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells.
    Anne P de Groot, Chelsea R Wilson, Ellen Weersing, Jacobine S Pouw, Albertina Dethmers-Ausema, Huong Nguyen, Evan F W Chen, Alok Shaurya, Linda Smit, Fraser Hof, Gerald de Haan.
      Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The polycomb group protein chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. Because leukemic cells are highly self-renewing, we tested whether pharmacological targeting of CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7 inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100052
  14. Blood Neoplasia. 2024 Dec;1(4): 100037
    Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.
    Sara H Small, Ricardo E Perez, Elspeth M Beauchamp, Aneta H Baran, Stephen D Willis, Mariafausta Fischietti, Michael Schieber, Masha Kocherginsky, Diana Saleiro, Leonidas C Platanias.
      Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal SLFN11 as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.
    DOI:  https://doi.org/10.1016/j.bneo.2024.100037
  15. Blood Neoplasia. 2025 Aug;2(3): 100100
    Ambroxol induces myeloma cell death by inhibiting autophagy.
    Yutaka Hattori, Hiromu Sugiyama, Yamato Miyashita, Shinsuke Shibata, Taiga Okaue, Yoshinao Matsumoto, Taketo Yamada, Tomofumi Yamamoto, Takashi Yamaguchi, Kohei Yamazaki, Hisako Kunieda, Hideyuki Saya, Maiko Matsushita.
      In the last decade, newly developed drugs have significantly improved the prognosis of patients with multiple myeloma (MM). However, most patients relapse sooner or later, and thus MM remains an incurable hematological malignancy. In addition, serious adverse events occasionally hamper the continuation of treatment. Exploitation of new drugs that potentiate antitumor activities and alleviate the adverse effects of existing drugs is needed. Here, we found through drug repositioning that ambroxol hydrochloride (ambroxol) induces apoptosis of MM cells. Interestingly, turnover and reporter assays revealed that ambroxol inhibits the late stage of autophagy. Transmission electron microscopy observation also revealed that MM cells treated with ambroxol accumulated autophagic vacuoles in the cytoplasm, further supporting the inhibition of late-stage autophagy. Existing anti-MM drugs demonstrate various effects on autophagy; panobinostat, a histone deacetylase inhibitor, induces autophagy, whereas bortezomib and lenalidomide do not. When administered together, ambroxol and panobinostat exhibited a synergistic antimyeloma effect, likely due to ambroxol inhibiting the activation of panobinostat-induced autophagy while downregulating MCL-1 expression. In the KMS11 xenograft model, ambroxol significantly delayed tumor growth when administered alone; when co-administered with panobinostat, ambroxol synergistically enhanced the panobinostat-induced inhibition of tumor growth. Interestingly, concomitant use of ambroxol and panobinostat alleviated panobinostat-induced diarrhea. Gene set enrichment and pathway analyses also revealed that ambroxol increased the expression of genes related to autophagy inhibition and unfolded protein response. These results suggested that autophagy is a promising therapeutic target for MM.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100100
  16. Blood. 2025 Jun 25. pii: blood.2025028560. [Epub ahead of print]
    Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer.
    Bernd Zeisig, Chiou-Tsun Tsai, Clemence Virely, Tsz Kan Kan Fung, Ali Tugrul Akin, Estelle Troadec, Bo Jiao, Richard Thompson, Priscilla Nga Ieng Lau, Nanjun Li, Andriani Charalambous, Larissa Bomfim, Jennifer Lynch, Athina Georgiou, Robbert Hoogeboom, Claire Lynn, Si Yi Zhang, Piers Em Patten, Cynthia Fisher, Anna Schuh, Seishi Ogawa, Ghulam J Mufti, Mohammad M Karimi, Chi Wai Eric So.
      Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting polycomb-group (PcG) epigenetic regulators, EZH2 and ASXL1 frequently found in haematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. While there is clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progresses. Here we show that genetic inactivation of Asxl1 and Ezh2 in murine haematopoietic stem/progenitor cells results in highly penetrant haematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and non-coding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF mutated cells, which create a novel vulnerability for PARP inhibitors (PARPi)-induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2 mutated cells are highly sensitive to PARPi that induce excessive DNA damage and significantly extend disease latency. Intriguingly the observed PARPi-sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target-site primed reverse transcription (TPRT) and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.
    DOI:  https://doi.org/10.1182/blood.2025028560
  17. Mol Cell. 2025 Jun 16. pii: S1097-2765(25)00499-X. [Epub ahead of print]
    BAG2 releases SAMD4B upon sensing of arginine deficiency to promote tumor cell survival.
    Meng-Ying Chen, Chun-Yu Sun, Ru Zhao, Xiao-Lin Guan, Miao-Lin Li, Fan Zhang, Zhi-Han Wan, Jing-Xuan Feng, Miao Yin, Qun-Ying Lei, Qi-Xiang Ma.
      Cells possess numerous metabolite sensors that detect essential nutrients for growth, with many directly binding to metabolites and responding to their levels. Given the vital role of arginine in various physiological and pathological processes, we hypothesized that there may be undiscovered sensors that detect arginine deficiency. Through a series of unbiased screening strategies in human cancer cell line models, we identified Bcl2-associated athanogene (BAG) family molecular chaperone regulator 2 (BAG2) as an arginine sensor, which could directly bind to arginine at the glutamine residue 167 (Q167). Upon arginine deficiency, BAG2 releases sterile alpha motif domain-containing protein 4B (SAMD4B), leading to β-catenin degradation to stabilize ATF4 protein, enhancing cell survival. When arginine is abundant, a strengthened binding between BAG2 and SAMD4B prevents β-catenin degradation, activating the Wnt/β-catenin pathway to support cell growth. Overall, our findings uncover an arginine-sensing pathway consisting of BAG2 and SAMD4B that promotes cancer cell adaptation to nutritional stress.
    Keywords:  BAG2; SAMD4B; arginine; cancer; metabolism; metabolite sensing; metabolite sensor
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.035
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