bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–05–10
twenty papers selected by
William Grey, University of York
  1. Metabolic Profiling and Perturbations of Human CD34+ Hematopoietic Stem and Progenitors to Regulate HSPC Function.
  2. Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
  3. Transposable elements shape stemness in normal and leukemic hematopoiesis.
  4. ATP2B1 expression identifies human hematopoietic stem cells with superior repopulation and self-renewal.
  5. MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2.
  6. Mutation of Tubgcp6 induces hematopoietic stem and progenitor cell exhaustion in zebrafish.
  7. Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.
  8. Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.
  9. NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac4C-independent mechanism.
  10. Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
  11. Hematopoietic Stem Cell-Based Cell and Gene Therapy Beyond Monogenic Diseases.
  12. Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
  13. Mass spectrometry-based single-cell proteomics technologies, trends, and biological insights.
  14. The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
  15. HSPCs and Treg cells cooperate to preserve extramedullary hematopoiesis under chronic inflammation.
  16. Humanized immune system animal models and their recent applications.
  17. Whole-genome doubling drives immune evasion by silencing antigen presentation.
  18. CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
  19. Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia.
  20. Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies.
  1. Blood Adv. 2026 May 06. pii: bloodadvances.2025018876. [Epub ahead of print]
    Metabolic Profiling and Perturbations of Human CD34+ Hematopoietic Stem and Progenitors to Regulate HSPC Function.
    Kai Yuan, Mingfang Xiong, Rong Yang, Keyu Sun, Zheng Zhang, Shiwei Zhang, Yanyu Xiu, Bo Cai, Jing Yang, Yan Ju, Hongyu Yin, Fei Liang, Yuying Sun, Guangyu Zhao, Yang Zeng.
      Hematopoietic stem cells (HSCs) possess self-renewal and multilineage differentiation abilities to generate blood cells and sustain hematopoiesis. Recent studies indicate that HSC metabolism is crucial for regulating their function and cell fate determination in mammals. However, a comprehensive understanding of the metabolic landscape of human HSCs across distinct developmental stages remains lacking. In this study, we performed untargeted metabolomics of Lin-CD34+ hematopoietic stem and progenitor cells (HSPCs) from human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM), revealing different developmentally associated metabolic signatures that shape HSPC function across ontogeny. Metabolomic analysis identified D-glutamine and arachidonic acid (AA) as metabolites exhibiting distinct abundance during HSPC development, suggesting their potential roles in modulating HSPC function. Transcriptomic profiling after specific metabolic treatment further revealed distinct gene expression programs associated with lineage commitment, stemness maintenance, and metabolic regulation. Functional assays demonstrated that the inhibition of glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) induced HSPCs into quiescent cell states, improving the engraftment of HSPCs and myeloid differentiation. Conversely, exogenous AA supplementation in HSPC culture promoted proliferation and significantly enhanced megakaryocytic differentiation both in vitro and in vivo. Collectively, our study profiled the metabolic landscape of human HSPCs from embryonic to adult period through the newborn stages, suggesting that metabolic modulation could regulate HSPC function. These findings provide novel mechanistic insights and potential strategies for metabolite-based interventions to promote and enhance human HSPC function, with broad implications for basic research and regenerative medicine.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018876
  2. Cell. 2026 May 01. pii: S0092-8674(26)00439-3. [Epub ahead of print]
    Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.
    Peng Lyu, Gaurav Agarwal, Chun-Jie Guo, Adam Sychla, Wallace Bourgeois, Tianyi Ye, Chen Weng, Mateusz Antoszewski, Samantha Joubran, Alexis Caulier, Michael Poeschla, Scott A Armstrong, Silvi Rouskin, Vijay G Sankaran.
      The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.
    Keywords:  HOXA9; SRSF2; clonal hematopoiesis; genetic variation; hematopoiesis; hematopoietic stem cell; leukemia; lncRNA; splicing
    DOI:  https://doi.org/10.1016/j.cell.2026.04.014
  3. Nat Genet. 2026 May 04.
    Transposable elements shape stemness in normal and leukemic hematopoiesis.
    Giacomo Grillo, Bettina Nadorp, Aditi Qamra, Bryce Drylie, Amanda Mitchell, Christopher Arlidge, Ankita Nand, Naoya Takayama, Alex Murison, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Andrea Arruda, Jean C Y Wang, Mark D Minden, Özgen Deniz, Héléna Boutzen, John E Dick, Mathieu Lupien.
      Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.
    DOI:  https://doi.org/10.1038/s41588-026-02585-z
  4. Proc Natl Acad Sci U S A. 2026 May 12. 123(19): e2604380123
    ATP2B1 expression identifies human hematopoietic stem cells with superior repopulation and self-renewal.
    Angelica Varesi, Murtaza S Nagree, Isabella Di Biasio, Andy G X Zeng, Sayyam Shah, Michael Zhang, Hyerin Kim, Alex Murison, Rohail Badami, Olga Gan, Liqing Jin, Jessica McLeod, Sheela A Abraham, Mark D Minden, Andrea Arruda, Igor Novitzky-Basso, Jonas Mattsson, John E Dick, Stephanie Z Xie.
      Long-term hematopoietic stem cells (LT-HSC) maintain lifelong hematopoiesis while preserving the stem cell compartment through self-renewal. The human LT-HSC compartment is molecularly and functionally heterogeneous and also varies across ontogeny. Dissecting the molecular basis for this variation is impeded by the paucity of immunophenotypic markers to resolve LT-HSC heterogeneity. Here, we identified ATPase plasma membrane calcium transporting 1 (ATP2B1/PMCA1) as a cell surface marker that is heterogeneously expressed by CD49f+ LT-HSC from fetal to adult hematopoiesis. ATP2B1 immunophenotypic expression stratified human CD49f+ LT-HSC from fetal liver, neonatal cord blood, and adult mobilized peripheral blood sources into functionally distinct subpopulations in single-cell (sc) clonogenic assays. CD49f+ATP2B1+ LT-HSC exhibited superior long-term repopulation and self-renewal capacities in vivo compared to CD49f+ATP2B1- LT-HSC. Molecular profiling by scMultiome and immunofluorescence microscopy point to enrichment of an HSC self-renewal program that includes the TFEB-endolysosomal axis in CD49f+ATP2B1+ LT-HSC. Our study provides a framework to dissect the heterogeneous molecular programs in LT-HSC.
    Keywords:  calcium; hematopoietic stem cell; lysosome
    DOI:  https://doi.org/10.1073/pnas.2604380123
  5. Leukemia. 2026 May 05.
    MECOM promotes leukemia progression and inhibits mast cell differentiation through functional competition with GATA2.
    Kohei Iida, Mayuko Nakanishi, Jakushin Nakahara, Shuhei Asada, Tomoya Isobe, Tomohiro Yabushita, Tsuyoshi Fukushima, Yosuke Tanaka, Manabu Ozawa, Yasuhiro Yamada, Toshio Kitamura, Keita Yamamoto, Susumu Goyama.
      MECOM is a transcription factor critical for the maintenance of hematopoietic stem cells (HSCs) and the pathogenesis of myeloid leukemia. Germline mutations clustered in the C-terminal zinc finger domain (ZFD) of MECOM are known to cause MECOM-associated syndromes, involving bone marrow failure and skeletal anomalies. However, the molecular consequences of these mutations and the precise downstream mechanisms of MECOM remain elusive. Here, we demonstrate that the C-terminal ZFD serves as the dominant DNA-binding module of MECOM, and that disease-associated mutations abrogate its DNA-binding capacity. Mechanistically, we reveal that MECOM functionally antagonizes GATA2 via C-terminal ZFD-mediated DNA binding and recruitment of the corepressor CtBP. This repression promotes myeloid leukemogenesis while suppressing mast cell differentiation. Furthermore, we generated a knockin mouse model harboring a C-terminal ZFD mutation, which successfully recapitulated the clinical phenotypes of MECOM-associated syndromes, including reduction of HSCs and B cells. Collectively, our findings define C-terminal ZFD mutations as loss-of-function mutations with impaired DNA binding, uncover the MECOM-GATA2 axis as a key regulatory pathway, and provide a valuable mouse model for understanding MECOM-associated syndromes.
    DOI:  https://doi.org/10.1038/s41375-026-02977-4
  6. Commun Biol. 2026 May 06.
    Mutation of Tubgcp6 induces hematopoietic stem and progenitor cell exhaustion in zebrafish.
    Yuxian Zhang, Li Li, Kemin Chen, Xiaohui Chen, Wei Liu, Wenqing Zhang, Zhibin Huang.
      Hematopoietic stem and progenitor cells (HSPCs) sustain blood cell production by balancing self-renewal and differentiation. While regulatory networks of transcription factors are well established during development of these cells, intrinsic cytoskeletal elements remain unclear. Here we show that the gamma-tubulin ring complex (γ-TuRC), a key regulator of microtubule nucleation, is essential for HSPC expansion in zebrafish. Forward genetic screening identifies the zebrafish smu1347 mutant, which exhibits HSPC exhaustion during definitive hematopoiesis. Positional cloning reveals a nonsense mutation in the tubgcp6 gene, encoding a core component of γ-TuRC, as responsible for the smu1347 phenotype. Mutation of Tubgcp6 causes mitotic arrest, disorganized spindle formation, and increased p53-dependent apoptosis. Time-lapse imaging and lineage tracing further demonstrate that Tubgcp6-deficient HSPCs preferentially undergo symmetric differentiation rather than self-renewal. Disrupting other γ-TuRC subunits (Tubgcp3, Tubgcp4, Tubgcp5) produces similar hematopoietic defects, underscoring the importance of intact microtubule nucleation for stem cell maintenance. These findings identify γ-TuRC-mediated microtubule organization as a critical regulator of HSPC fate and suggest that Tubgcp6 may represent a potential therapeutic target for bone marrow failure syndromes and stem cell exhaustion disorders.
    DOI:  https://doi.org/10.1038/s42003-026-10209-9
  7. Blood. 2026 May 08. pii: blood.2025031474. [Epub ahead of print]
    Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.
    Chang Xu, Xue Lv, Shangda Yang, Yanling Lv, Yawei Zheng, Yu-Xiang Wang, Yan Hui, Guohuan Sun, Xiangnan Zhao, Lan-Yue Ma, Honglin Duan, Linmin Zhang, Shuangshuang Pu, Lu Sun, Xialin Li, Yicheng He, Wenjia Fang, Meng Yang, Toshio Suda, Qi Chen, Tao Cheng, Hui Cheng.
      Hematopoietic stem cells (HSCs) rely on specialized niche cells for maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. Here, we identified a subset of Procr+ endothelial cells (ECs) with progenitor-like properties in bone marrow (BM), which is critical for vascular homeostasis and injury regeneration. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr serves dual biological functions as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds HSPA8 to promote Foxc2 nuclear translocation, upregulating Dll4 transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC crosstalk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSCs Notch signaling, coordinating their adipogenic-osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ EPCs in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights Procr⁺ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.
    DOI:  https://doi.org/10.1182/blood.2025031474
  8. Blood. 2026 May 07. pii: blood.2025031836. [Epub ahead of print]
    Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.
    Abhishek K Singh, Kathrine S Rallis, Jose A Cancelas.
      Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca²⁺ overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2025031836
  9. Nat Cell Biol. 2026 May 04.
    NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac4C-independent mechanism.
    Weiqian Li, Yue Huo, Zhaoru Zhang, Yiyang Liu, Xinyue Qian, Jia Ouyang, Rao Gu, Chenxi Han, Shuo Li, Rui Su, Jia Yu, Pengxu Qian, Fang Wang.
      Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3' untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, Nat10 deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3' untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation-an effect independent of NAT10's ac4C catalytic activity. Moreover, NAT10 dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.
    DOI:  https://doi.org/10.1038/s41556-026-01949-1
  10. Cell Stem Cell. 2026 May 07. pii: S1934-5909(26)00152-9. [Epub ahead of print]
    Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.
    Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Ines Bergerweiss, Karolin Stumpf, Barbara Betz, Susanna Gabrowski, Frank Y Huang, Maria-Eleni Lalioti, Bendix Hempel, Markus Sohn, Heikki Kuusanmäki, Vera Thiel, Julia M Unglaub, Rabia Shahswar, Sarah Richter, Maike Janssen, Darja Karpova, Elisa Donato, Halvard Bonig, Christoph Röllig, Simon Raffel, Michael Heuser, Michael Hundemer, Mika Kontro, Ann-Kathrin Eisfeld, Tim Sauer, Nina Cabezas-Wallscheid, Carsten Müller-Tidow, Andreas Trumpp.
      The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.
    Keywords:  BCL-2; MAC-score; acute myeloid leukemia; azacitidine; chemotherapy; leukemic stem cells; personalized medicine; plasticity; therapy resistance; venetoclax
    DOI:  https://doi.org/10.1016/j.stem.2026.04.012
  11. Stem Cells Dev. 2026 May 04. 15473287261444631
    Hematopoietic Stem Cell-Based Cell and Gene Therapy Beyond Monogenic Diseases.
    Masayuki Kai, Fulvio Mavilio.
      Hematopoietic stem cells (HSCs) are multipotent stem cells capable of differentiating into all types of blood and immune progeny and endowed with self-renewal capacity to enable lifelong hematopoiesis. Based on these unique characteristics, HSCs are utilized as a cell source for cell and gene therapies. During its dawning period, HSC-based therapies faced significant challenges due to inefficient gene transfer and insertional leukemogenesis. However, technological advances, such as the use of HIV-derived lentiviral vectors and cellular promoters, have established HSC gene therapy as a powerful treatment modality for patients with congenital monogenic diseases, leading to approved therapies commercially available in Europe and the United States. HSC-based therapies are now being explored for broader indications, including cancer, autoimmune, and infectious diseases. Innovative concepts achievable with HSCs-such as delivering therapeutic proteins to hard-to-reach tissues, in vivo delivery of antibodies and immune cells, and molecular shielding-have been proposed, offering new therapeutic approaches. Moreover, technological innovations in related fields, including more precise gene expression control and reduced-toxicity bone marrow conditioning, are expanding the range of applications. HSC-based cell and gene therapies are therefore evolving into a therapeutic modality applicable beyond monogenic diseases to a broader range of indications, to provide therapeutic value to patients with intractable diseases.
    Keywords:  beyond monogenic; cell and gene therapy; hematopoietic stem cells
    DOI:  https://doi.org/10.1177/15473287261444631
  12. Blood Adv. 2026 May 05. pii: bloodadvances.2025016208. [Epub ahead of print]
    Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.
    Nastassja Keora Scheidegger, Constanze Schneider, Gabriela Alexe, Yi-Cheng Wang, Todd A Alonzo, Allen Basanthakumar, Wallace A Bourgeois, Julia Dudkiewicz-Garbicz, Delan Khalid, Lucy A Merickel, Jennifer A Perry, Rhonda E Ries, Silvi Salhotra, Audrey Taillon, Alan S Gamis, Richard Aplenc, Marian H Harris, Mark Wunderlich, Scott A Armstrong, Jessica A Pollard, Soheil Meshinchi, Yana Pikman, Kimberly Stegmaier.
      KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of AML cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission (CR) rate, poor event-free (EFS) and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, apoptosis and downregulation of Myc targets in the combination compared to each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden compared to single drug treatments, but without improving overall survival compared to menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016208
  13. Trends Biochem Sci. 2026 May 07. pii: S0968-0004(26)00111-8. [Epub ahead of print]
    Mass spectrometry-based single-cell proteomics technologies, trends, and biological insights.
    Rui Hu, Christian Montes, Justin W Walley.
      Single-cell proteomics (SCP) has emerged as a transformative approach for characterizing cellular heterogeneity at the protein level. Recent advances in mass spectrometry workflows, with improvements spanning sample preparation, peptide separation, data acquisition, and data interpretation, have enabled unprecedented proteome depth and throughput at single-cell resolution. Beyond technological innovations, SCP is now addressing complex biological questions in oncology, developmental biology, and neuroscience, revealing dynamic cellular states and regulatory mechanisms. Integration with other single-cell omics is bridging the gap between genotype-phenotype relationships and uncovering multilayered regulation. In this review, we summarize recent progress in SCP technologies and highlight emerging applications and integrative strategies that mark a transition from technological development to broad biological understanding.
    Keywords:  cellular heterogeneity; mass spectrometry; multiomics; single-cell proteomics
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.011
  14. Cancer Lett. 2026 Apr 30. pii: S0304-3835(26)00320-4. [Epub ahead of print] 218557
    The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
    Xiaofeng Kang, Guanglin Lei, Xiaobo Hou, Yimeng Du, Minghao Xu, Chunyuan Xue, Donghui Liu, Songhao Jia, Jingbo Shan, Chuanhao Tang, Xiaojie Xu, An Xu.
      Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90+/EpCAM+ cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.
    Keywords:  BTN3A3; Cancer stemness; Hepatocellular carcinoma; Sorafenib resistance; TOMM22
    DOI:  https://doi.org/10.1016/j.canlet.2026.218557
  15. Sci Adv. 2026 May 08. 12(19): eadv9351
    HSPCs and Treg cells cooperate to preserve extramedullary hematopoiesis under chronic inflammation.
    Maria Kuzmina, Srdjan Grusanovic, Jiri Brezina, Flavian Thelen, Karolina Vanickova, Mirko Milosevic, Irina Ribeiro Bas, Nataliia Pavliuchenko, Sarka Ruzickova, Jakub Rohlena, Dominik Filipp, Katerina Rohlenova, Cesar Nombela-Arrieta, Tomas Brdicka, Meritxell Alberich-Jorda.
      Hematopoietic stem and progenitor cells (HSPCs) are localized within specialized niches of the bone marrow (BM). However, during hematological disorders or infections, the functionality of these cells in the BM is compromised, leading to extramedullary hematopoiesis (EMH). Chronic inflammation drives EMH, yet its impact on HSPCs outside the BM is poorly understood. Using a mouse model of chronic autoinflammatory disease, we demonstrated the presence of extramedullary HSPCs in blood, spleen, and inflamed tails and paws. Single-cell transcriptomics revealed a unique expression profile in extramedullary HSCs, with significant up-regulation of Cd53, MHCII-associated, and immunosuppressive genes. We further demonstrated that extramedullary CD53+ HSPCs act as antigen-presenting cells, promoting the development of regulatory T cells (Treg cells) to control chronic inflammation at extramedullary sites. Conversely, Treg cells exert a protective role on extramedullary HSPCs. Together, our findings revealed a mutually supportive relationship between a unique subset of HSPCs and T cells in inflamed tissues during chronic inflammation.
    DOI:  https://doi.org/10.1126/sciadv.adv9351
  16. Animal Model Exp Med. 2026 May 06.
    Humanized immune system animal models and their recent applications.
    Nicolas Skuli, Rudra B Amin, A'ishah Bakayoko, Marisa Kruidenier, Sahara Aqui, Sarah J Skuli, Terence P Gade.
      Human or humanized immune system (HIS) animal models have emerged as indispensable tools for studying human biology and disease in vivo. By engrafting human hematopoietic and hematopoietic stem cells (HSC) into immunodeficient hosts, these models have enabled the development of a functional HIS, allowing the study of immune responses, disease mechanisms, and therapeutic interventions in a physiologically relevant setting. HIS models have broad applications across cancer research, infectious disease, regenerative medicine, and immunotherapy development. This review provides a comprehensive overview of the current landscape of HIS model generation, including HSC-based approaches, host strain selection, and recent advances involving genetically engineered mouse models expressing human cytokines and human leukocyte antigen molecules. We evaluated the strengths and limitations of these models, including issues with incomplete immune reconstitution and species-specific incompatibilities. We also discuss their increasing role in preclinical drug development and explore emerging innovations such as multitissue humanization and genome-editing strategies. As HIS models continue to evolve, they provide strong opportunities to bridge basic research and clinical translation.
    Keywords:  animal science; humanized mice; immunotherapy; patient‐derived xenografts; vaccines
    DOI:  https://doi.org/10.1002/ame2.70212
  17. Cancer Cell. 2026 May 07. pii: S1535-6108(26)00218-7. [Epub ahead of print]
    Whole-genome doubling drives immune evasion by silencing antigen presentation.
    Pierre Foidart, Zheqi Li, Xinran Cai, Marco Seehawer, Daniel D Brown, Amatullah Tawawalla, Pilar Baldominos, Salma Parvin, Jun Nishida, Ernesto Rojas-Jimenez, Triet M Bui, Benedetto Diciaccio, Rahul Kumar, Brent T Schlegel, Marie-Anne Goyette, TashJae Scales, Pengze Yan, Xintao Qiu, Rong Li, Yijia Jiang, Yingtian Xie, Mahmoud Aarabi, Xiao-Yun Huang, Laura E Stevens, Paloma Cejas, Lise Mangiante, Cristina Irene Sotomayor Vivas, Kathleen E Houlahan, Christina Curtis, Steffi Oesterreich, Isaac S Harris, Anthony G Letai, Adrian V Lee, Henry W Long, Judith Agudo, Kornelia Polyak.
      Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.
    Keywords:  antigen presentation; breast cancer; epigenetic silencing; immune escape; whole genome doubling
    DOI:  https://doi.org/10.1016/j.ccell.2026.04.007
  18. Transl Oncol. 2026 May 07. pii: S1936-5233(26)00140-3. [Epub ahead of print]69 102803
    CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
    Rui Cao, Ling-Ling Zhou, Qi Liu, Guo-E Liu, Ling Xu, Han He.
       BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options, especially in cases of relapse or refractory disease. Metabolic reprogramming, particularly fatty acid oxidation (FAO), has emerged as a critical mechanism in AML progression. Carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting enzyme in mitochondrial FAO, is highly expressed in metabolically active tissues, yet its role in AML remains poorly defined.
    METHODS: CPT1B expression was analyzed using TCGA datasets, patient samples, and AML cell lines. Functional studies employed CPT1B knockdown (shRNA) and overexpression (lentiviral) models in AML cell lines (THP-1, KG-1, HL-60, HEL). In vitro and in vivo effects were assessed via CCK-8, flow cytometry, western blot, ELISA, and xenograft models in immunodeficient mice. The FAO inhibitor Etomoxir was used to evaluate metabolic dependency.
    RESULTS: CPT1B was significantly overexpressed in AML tissues and cell lines compared to normal controls and correlated with poorer overall survival. CPT1B knockdown reduced proliferation, induced G0/G1 cell cycle arrest, and promoted apoptosis in AML cells. CPT1B silencing inhibited tumor growth and dissemination in vivo. Conversely, CPT1B overexpression enhanced FAO activity, increased lipid droplet accumulation, and upregulated PPARA, CPT1A, and ACOX1 expression. Treatment with Etomoxir reversed these effects, restoring apoptosis and inhibiting CPT1B-driven proliferation both in vitro and in mouse models.
    CONCLUSIONS: CPT1B acts as a key metabolic driver of AML progression through FAO-dependent lipid metabolic reprogramming. Its inhibition suppresses leukemic growth and improves survival outcomes, identifying the CPT1B-FAO axis as a promising therapeutic target and prognostic biomarker in AML.
    Keywords:  Acute myeloid leukemia; Apoptosis; CPT1B; Etomoxir; Fatty acid oxidation; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.tranon.2026.102803
  19. Sci Transl Med. 2026 May 06. 18(848): eadv8951
    Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia.
    Ping Liu, Sulin Zhang, Bing-Yi Chen, Binhe Chang, Yilun Jiang, Xiya Li, Xinchi Chen, Zi-Juan Li, Ruirui Yang, Xiaoning Wang, Chun-Hui Xu, Xiaomeng Liu, Na Liu, Yuanyuan Jia, Peng-Cheng Yu, Yong Wang, Li-Juan Zong, Cheng-Long Hu, Hui Hou, Duanhua Cao, Xutong Li, Chu-Han Deng, Yi-Yi Ren, Mu-Ying Zhao, Xinyi Ma, Rongrong Cui, Dan Teng, Miao Chen, Roujia Wang, Jiacheng Jin, Shi-Yu Jiang, Xiaojing Yan, Kai Xue, Qunling Zhang, Jianfeng Li, Enyong Dai, Shuhong Shen, Zhikai Wang, Xueshi Ye, Jin Zhang, Yu Liu, Wenguo Cui, Min Lu, Wei-Li Zhao, Chun-Kang Chang, Peng-Cheng He, Zhu Chen, Sai-Juan Chen, Mingyue Zheng, Xiao-Jian Sun, Lan Wang.
      Leukemia is a malignant tumor with a high recurrence rate and poor prognosis for patients. Thus, there is an urgent need to explore new therapeutic targets that play critical roles in leukemogenesis but have little effect on normal hematopoietic cells. Here, we show that RNA binding protein with multiple splicing (RBPMS), which is highly expressed in acute myeloid leukemia (AML) and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS inhibits self-renewal of leukemia-initiating cells (LICs) and leukemia development but has little effect on normal hematopoiesis. Mechanistically, RBPMS recruits the N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which promotes the stability of the forkhead box O1 (FOXO1) mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by directly binding to FOXO1 and promoting FOXO1-regulated glycolysis. Overexpression of FOXO1 has been shown to reverse RBPMS inhibition-induced phenotypes in both leukemic cells and mouse models. We also designed a specific inhibitor of RBPMS that has therapeutic effects in AML patient-derived xenograft (PDX) models. We therefore highlight RBPMS as a promising drug target for leukemia therapy.
    DOI:  https://doi.org/10.1126/scitranslmed.adv8951
  20. Blood. 2026 May 08. pii: blood.2025030891. [Epub ahead of print]
    Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies.
    Lucia Y Chen, Adolfo Aleman, Marta Larrayoz, Hsiling Chiu, Junfei Zhao, Oliver Van Oekelen, Geoffrey Kelly, Seunghee Kim-Schulze, Alessandro Lagana, Sundar Jagannath, Tracy T Chow, Teresa Lozano, Juan J Lasarte, Joseph C Hamley, Warren Baker, Benjamin L Ebert, Udo Oppermann, Michael D Amatangelo, Anita Krithivas Gandhi, Patrick Ryan Hagner, Jose A Martínez-Climent, Sarah Gooding, Thomas A Milne, Samir Parekh.
      T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.
    DOI:  https://doi.org/10.1182/blood.2025030891
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