bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–06–21
twelve papers selected by
William Grey, University of York
  1. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  2. Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.
  3. Aging of hematopoietic stem cells is inconsequential to progenitor cell function.
  4. Plasmin-mediated fibrinolysis is required for hematopoietic recovery after 5-FU-induced myeloablation.
  5. A Reliable Method for Thawing Primary AML and CMML Mononuclear Cells to Preserve Viability and Function.
  6. ABO: A 3D stroma-supported culture platform enabling full human B-lymphopoiesis for disease modeling and gene therapy development.
  7. Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.
  8. Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman-Diamond syndrome.
  9. Mass spectrometry proteomics for studying mitostasis.
  10. Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS.
  11. The search for safe and effective CAR-T targets in AML.
  12. From cell lines to PDXs: in vivo confirmation of synergistic drug responses identified in leukemia cell line models.
  1. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
    Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.
      Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  2. Cell Stem Cell. 2026 Jun 18. pii: S1934-5909(26)00199-2. [Epub ahead of print]
    Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.
    James W Swann, Jun Hou Fung, Ziwei Chen, Oakley C Olson, Amélie Collins, Tenzin Lhakhang, Melissa A Proven, Ruiyuan Zhang, Raul Rabadan, Emmanuelle Passegué.
      Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.
    Keywords:  acute myeloid leukemia; differentiation; emergency myelopoiesis; hematopoietic stem and progenitor cell; inflammation; quantitative model; regeneration; topology
    DOI:  https://doi.org/10.1016/j.stem.2026.05.007
  3. Stem Cell Reports. 2026 Jun 18. pii: S2213-6711(26)00176-1. [Epub ahead of print] 102965
    Aging of hematopoietic stem cells is inconsequential to progenitor cell function.
    Jenna Myers, Atesh K Worthington, Donna M Poscablo, Paloma Medina, Saran Chattopadhyaya, Raana Mogharrab, Marcel G E Rommel, E Camilla Forsberg.
      Aging of the hematopoietic system has profound consequences for organismal health and longevity, attributed to the well-characterized functional aging of hematopoietic stem cells (HSCs). Here, we tested whether progenitor cells may demonstrate age resistance to enable hematopoietic homeostasis throughout life despite the functional decline of upstream HSCs. Strikingly, our results revealed unwavering reconstitution capacity by young and old progenitors, demonstrating that intermediate progenitors are functionally unaffected by aging and placing Flk2+ multipotent progenitors (MPPFs) as a potential source of age resilience. This unique finding was emphasized by unchanged transcriptomic, proliferation, and mitochondrial capacity of young and old MPPFs, revealing remarkable similarities upon aging. Considering that HSCs functionally decline with age, yet intermediate progenitors remain unperturbed and "age resilient", we posit that MPPFs may play an essential role in protecting downstream progenitors from inheriting age-related properties from HSCs. We propose three potential mechanisms for how MPPFs maintain hematopoietic integrity and homeostasis with age.
    Keywords:  age resilience; aging; aging homeostasis; hematopoietic progenitor cells; hematopoietic reconstitution; hematopoietic stem cells; longevity; multipotent progenitor cells; single-cell RNA sequencing; transcriptomics; transplantation
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102965
  4. Blood Adv. 2026 Jun 18. pii: bloodadvances.2025019416. [Epub ahead of print]
    Plasmin-mediated fibrinolysis is required for hematopoietic recovery after 5-FU-induced myeloablation.
    Tiffany Phuc Linh Nguyen, Yong Guang Jiang, Betul M Ogan, Andrew D Doyle, Duy T Tran, Jerrold M Ward, Andrew Zhang, Rafaela Ferrer de Oliveira, Francesca Ferraresso, Jacob R Bledsoe, Christian J Kastrup, Matthew J Flick, R Grant Rowe, Thomas H Bugge, Lakmali M Silva.
      Hematopoietic recovery following myeloablation plays a critical role in the survival of the patients that receive chemotherapy or hematopoietic stem cell transplantation. Understanding the mechanisms underlying hematopoiesis helps identify molecular and/or cellular determinants that could be targeted to enhance hematopoietic recovery. Although several mechanisms by which the plasminogen activation system promotes hematopoietic recovery after myelosuppression have been reported, the specific role fibrinolysis plays in hematopoietic recovery is unclear. The current study employs 5-Fluorouracil-mediated myeloablation in murine models and provides a clear demonstration of uniform extravascular fibrin deposits in the bone marrow niche upon myeloablation. Persistent fibrin deposits in plasminogen-deficient mice lead to failure of hematopoietic recovery. Genetic and pharmacological depletion of fibrinogen following myeloablation restored hematopoietic recovery, revealing the critical role of fibrin in this process. Moreover, defective fibrinolysis led to delayed hematopoietic recovery via a mechanism that involves fibrin engagement with the major myeloid integrin aMb2. Importantly, similar fibrin-rich marrow niches were also observed in human bone marrow injury and failure states. The study identifies a novel molecular pathway that could be therapeutically targeted to enhance hematopoietic recovery following myeloablation.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019416
  5. Bio Protoc. 2026 Jun 05. 16(11): e5720
    A Reliable Method for Thawing Primary AML and CMML Mononuclear Cells to Preserve Viability and Function.
    Kelly Lim, Verity Saunders, Monika Kutyna, Nirmal Robinson, Devendra Hiwase, Daniel Thomas.
      Human mononuclear cells derived from peripheral blood and bone marrow are valuable resources for the study of hematological malignancies, including acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Cryopreservation enables long-term storage of patient samples for downstream assays; while thawing protocols have been described, subsequent recovery of viable cells after thawing can be challenging, particularly for fragile blast and monocyte populations. Here, we describe a reliable protocol for thawing cryopreserved AML and CMML mononuclear cells designed to preserve post-thaw viability, recovery, and functional integrity. The method incorporates controlled dilution of cells out of cryoprotectant with anticoagulant-supplemented thaw buffer, DNase I treatment, and gentle resuspension steps. Using this approach, post-thaw viability consistently exceeded 80% with a mean recovery of 55.6% across samples. Recovered cells retained functional capacity, as demonstrated by colony-forming assays, and maintained immunophenotypic characteristics by flow cytometry. This protocol provides a robust and reproducible method for the recovery of cryopreserved AML and CMML mononuclear cells and may be broadly applicable to other fragile or monocyte-rich patient-derived hematopoietic samples. Key features • Reliable thawing protocol that preserves viability and recovery of cryopreserved AML and CMML mononuclear cells. • Controlled dilution with anticoagulant supplementation, DNase I treatment, and gentle resuspension minimizes cell aggregation of fragile blast and monocyte populations. • Maintains cell functional capacity and immunophenotypic characteristics for downstream assays. • Applicable to cryopreserved patient-derived mononuclear cells prone to aggregation, low recovery, or poor viability with conventional thawing.
    Keywords:  AML; CMML; Cryopreserved; Leukemia; Monocyte; Mononuclear cells; Thaw; Viability
    DOI:  https://doi.org/10.21769/BioProtoc.5720
  6. Cell Rep Med. 2026 Jun 18. pii: S2666-3791(26)00296-X. [Epub ahead of print] 102879
    ABO: A 3D stroma-supported culture platform enabling full human B-lymphopoiesis for disease modeling and gene therapy development.
    Merijn Braams, Martijn Cordes, Sandra A Vloemans, Bas de Mooij, Sandra de Bruin-Versteeg, Ashley Wachtmeester, Anton W Langerak, Karin Pike-Overzet, Frank J T Staal, Kirsten Canté-Barrett, Sander de Kivit.
      Defective B cell development underlies a large proportion of inborn errors of immunity. Progress in understanding disease mechanisms and therapy development remains limited because current human in vitro models incompletely recapitulate B-lymphopoiesis. We present a three-dimensional aggregate culture platform composed of human hematopoietic stem and progenitor cells (HSPCs) and mouse bone marrow (BM) stromal cells as an assay for efficient B cell output (ABO). ABOs support progression through pro-B, pre-B, immature, and transitional B cell stages, with a transcriptional profile and B cell receptor (BCR) repertoire diversity resembling human B cell ontogeny. ABO-derived B cells exhibit functional BCR signaling and differentiate into class-switched memory B cells and antibody-secreting cells following CD40-mediated stimulation. ABOs reproduce the B cell developmental arrest observed in HSPCs from patients with RAG1-deficient severe combined immunodeficiency (SCID), which is corrected by a RAG1 gene therapy lentiviral vector. Thus, ABOs provide a clinically relevant platform for modeling B cell immunodeficiencies and evaluating therapeutic strategies.
    Keywords:  B cell development; RAG1 deficiency; bone marrow stromal cells; gene therapy; hematopoietic stem and progenitor cells; inborn errors of immunity; severe combined immunodeficiency
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102879
  7. Cell Rep. 2026 Jun 16. pii: S2211-1247(26)00629-7. [Epub ahead of print]45(6): 117551
    Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.
    Giancarlo Gonzalez-Areizaga, Sherry T Shu, John J Alvarado, Haibin Shi, Li Chen, Thomas E Smithgall.
      Acute myeloid leukemia is often associated with constitutive activation of the Src-family kinases, Hck, Lyn, and Fgr. Their modular SH3 and SH2 domains regulate kinase activity and signal transduction. Here, we show that regulatory domain dynamics critically influence both inhibitor sensitivity and leukemogenic signaling. We modified the Fgr SH2-kinase linker to enhance intramolecular SH3 engagement, shifting the conformational ensemble to the closed state. This shift increased the Km for ATP and enhanced the potency of ATP-site inhibitors in vitro. Human myeloid cells expressing these constrained Fgr variants exhibited heightened sensitivity to ATP-site inhibitors in terms of growth arrest. These cells also demonstrated impaired bone marrow engraftment in vivo, suggesting a key role for Fgr dynamics and SH3-dependent signaling in leukemia cell survival within this niche. Small molecules that similarly restrict Src-family kinase regulatory domain dynamics may provide a new therapeutic approach to AML and other cancers linked to these kinases.
    Keywords:  CP: cancer; CP: molecular biology; Fgr; SH2 domain; SH3 domain; Src-family kinase; acute myeloid leukemia; allostery; tyrosine kinase
    DOI:  https://doi.org/10.1016/j.celrep.2026.117551
  8. Hemasphere. 2026 Jun;10(6): e70374
    Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman-Diamond syndrome.
    Laura Langohr, Ilse Kaaja, Suvi P M Douglas, Hanna Nebelung, Jessica Koski, Ina Ikonen, Lotta Katainen, Katri Maljanen, Marja Hakkarainen, Tuulia Räisänen, Riitta Niinimäki, Sakari Kakko, Timo Siitonen, Sadiksha Adhikari, Markus Vähä-Koskela, Caroline A Heckman, Jenni Lahtela, Ulla Wartiovaara-Kautto, Esa Pitkänen, Outi Kilpivaara.
      ERCC6L2 disease (ED) is a rare bone marrow failure syndrome caused by biallelic germline mutations in ERCC6L2. ED leads to the accumulation of somatic TP53 mutations, myelodysplastic syndrome, and acute myeloid leukemia (AML) with erythroid predominance and poor prognosis. While ERCC6L2 is implicated in DNA replication and repair, the transcriptomic events underlying delayed erythropoiesis and leukemic progression remain largely undefined. To delineate these processes, we leverage bulk and single-cell transcriptomics of patient fibroblasts, bone marrow, and peripheral blood across disease stages, including single-cell TP53 genotyping. We identify disease-associated erythroid dysregulation and ferroptotic stress emerging prior to TP53 mutation, highlighting an early vulnerability in ED leukemogenesis. We compare ED to Shwachman-Diamond syndrome (SDS) to reveal shared and disease-specific transcriptional programs. TP53 mutations in ED and SDS arise in hematopoietic stem and progenitor cells but do not independently drive changes in cell cycle or stress pathways during erythropoiesis, despite harboring distinct germline defects. Both diseases converge in late erythropoiesis into a stress state characterized by ferroptotic signaling, G1 arrest, and BCL2L1 upregulation. As a disease-specific pattern, ED shows aberrant erythroid priming with TP53-driven differentiation arrest shaping progression toward erythroid leukemia. Thereby, we establish the first patient-level single-cell map of ED and provide a curated resource for future work on ED, SDS, and TP53-driven leukemogenesis. Overall, our findings in pre-malignant ED offer a window into early alterations leading to high-risk leukemia.
    DOI:  https://doi.org/10.1002/hem3.70374
  9. Protein Sci. 2026 Jul;35(7): e70673
    Mass spectrometry proteomics for studying mitostasis.
    Lakshita Sharma, Sristi Chakroborty, Hirak Das, Silke Oeljeklaus, Julian Bender, Bettina Warscheid.
      Maintaining mitochondrial integrity and function is fundamental to cellular homeostasis. Cells rely on coordinated protein quality control (QC) systems-including intricate chaperone-protease networks, the ubiquitin-proteasome system, and cytosolic surveillance pathways-that together form a dynamic, cell-wide mitostasis network governing the import, folding, synthesis, and degradation of mitochondrial proteins. Disruption of mitochondrial homeostasis, for example, by impairing mitochondrial protein import, induces proteotoxic stress and contributes to human disease. Mass spectrometry (MS)-based proteomics has established itself as an indispensable method to dissect mitostasis at unprecedented depth by enabling systematic quantitative analysis of protein abundance, localization, interactions, stability, and dynamics. In this review, we highlight state-of-the-art MS technologies and multifaceted proteomics approaches used to study mitostasis on a proteome-wide level. These functional analysis approaches build on quantitative MS methods employing label-free, metabolic, and chemical labeling strategies, which allow precise tracking of proteome dynamics in response to different cellular conditions including stress. Spatial and interaction-based approaches, such as affinity purification-MS, proximity labeling, and complexome profiling, provide detailed insight into the organization and regulation of the complex mitochondrial organizing system, chaperone networks, and protein QC pathways. Furthermore, we discuss advanced methodologies such as nascent chain and dynamic proteomics strategies, which offer a proteome-wide comprehension of early stress responses and fast regulation. The skillful integration of temporal, spatial subcellular, interaction, nascent, and dynamic proteomics approaches now enables a systems-level assessment of mitostasis, paving the way for a holistic while nuanced understanding of this essential cellular process and the underlying molecular mechanisms.
    Keywords:  complexome profiling; dynamic SILAC; interactome analysis; mitochondria; nascent proteomics; protein import stress; proteome dynamics; proteostasis; proximity labeling; quantitative mass spectrometry
    DOI:  https://doi.org/10.1002/pro.70673
  10. Blood. 2026 Jun 18. pii: blood.2025030731. [Epub ahead of print]
    Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS.
    He Tian Tony Chen, Pratik Joshi, Severine Cathelin, Soheil Jahangiri Tazehkand, Saeer A Adeel, Joshua Xu, Emily Tsao, Yulin Mo, David Kealy, Adam Dowle, Zaldy Balde, Marry Xuan, Dylan Gowlett-Park, Katarina Czibere, Alexandra Misura, Olga Bigun, Renato Sasso, August Lin, Noor Kundu, Dianne Chadwick, Sila Usta, Tina Khazaee, Signy Chow, Hubert Tsui, Mark D Minden, Andrew N Holding, Katherine S Bridge, Gang Zheng, Kristin Hope.
      Myelodysplastic neoplasms (MDS) feature hematopoietic deficits driven in part by transcript splicing abnormalities. Thus far, such disease-driving transcripts have been identified in association with specific splicing factor mutations. However, conserved aberrant splicing-derived transcripts that drive MDS independently of mutational status remain poorly studied despite representing global therapeutic targets. Here, we characterize an MDS-associated MBD1 isoform (MBD1-L) as a novel member of this class of transcripts. Rather than originating from a mutant splicing factor, the abnormal production of MBD1-L is driven by reduced WTAP expression in MDS. Overexpression of MBD1-L in healthy human HSPCs recapitulates archetypal MDS defects, including reduced terminal GLYA+ erythroid differentiation, suppressed cell cycling and impaired in vivo reconstitution capacity during increased hematopoietic demand in xenotransplantation assays. An integrated multiomics approach assessing DNA binding of MBD1 isoforms, and resulting changes in chromatin accessibility, histone mark deposition and transcriptional changes, revealed that these defects arise from an isoform-specific switching of MBD1's binding behavior. The MBD1-L isoform refocuses MBD1-L's heterochromatin-promoting activity from methylated to unmethylated CpGs and thus enacting broad downregulation of CpG-rich promoters as well as secondary epigenetic effects mediated by its downstream target BCOR. Remarkably, we also find that directly reversing abnormal MBD1 splicing across a broad range of primary human MDS samples using nanoparticle-encapsulated ASOs enhances in vitro erythroid differentiation, supporting the utility of RNA therapies for MDS treatment. Thus, our findings demonstrate MBD1-L to be a global, disease-driving splice variant across MDS, and illustrate the potential for RNA-based therapies in the broad treatment of MDS.
    DOI:  https://doi.org/10.1182/blood.2025030731
  11. Blood Cancer J. 2026 Jun 20.
    The search for safe and effective CAR-T targets in AML.
    Florian Van Oers, Donovan Flumens, Simon Haentjens, Laurens Krekelbergh, Sébastien Anguille.
      Acute myeloid leukemia (AML) remains a highly aggressive malignancy with limited therapeutic options and poor long-term survival. A major barrier to curative treatment is the persistence of leukemic stem cells (LSCs), a chemo-resistant population that drives relapse. Chimeric antigen receptor (CAR)-T-cell therapy has transformed the treatment of B-cell hematological malignancies. However, its application in AML has been met with significant challenges. Among the key challenges are the scarcity of AML-specific antigens and the risk of on-target/off-tumor toxicity due to shared antigen expression on normal hematopoietic stem cells (HSCs) and/or mature blood cells. Early clinical trials of CAR-T-cell therapy in AML -primarily targeting CD123, CD33, or CLL‑1- have demonstrated limited durable complete remissions and/or frequent myeloablation, underscoring the need for more selective targets. While other targets show more restricted expression profiles, they are often expressed only in a small subgroup of AML patients. In this review, we systematically evaluated 63 AML-associated antigens for which CAR constructs have been reported, using five criteria: (1) homogeneous expression across AML patients, (2) uniform expression on AML cells within individual patients; (3) presence on LSCs, (4) absence on normal HSCs, and (5) no or acceptable expression on mature blood cells. Applying a 20-point scoring framework, 13 novel antigens emerged as the most promising candidates for CAR-T-cell therapy in AML: ADGRE2, SIGLEC-6, IL1RAP, MUC1, CCR1, CD155, CD70, LILRB4, GRP78, CD37, ITGB2, TIM-3 and mesothelin. We discuss the advantages and limitations of each target, along with strategies to mitigate associated risks. With no CAR-T-cell therapy currently approved for AML, this comprehensive review provides a prioritized antigen landscape and a framework to guide the rational design of next-generation CARs for this challenging malignancy.
    DOI:  https://doi.org/10.1038/s41408-026-01544-5
  12. Blood Neoplasia. 2026 Aug;3(3): 100230
    From cell lines to PDXs: in vivo confirmation of synergistic drug responses identified in leukemia cell line models.
    Tamara C A I Verbeek, Kirsten S Vrenken, Susan T C J M Arentsen-Peters, Emma van den Hoof, Rob Pieters, Ronald W Stam.
      Despite recent advances in clinical outcome for infants diagnosed with KMT2A-rearranged acute lymphoblastic leukemia (ALL), the development of more effective and less toxic induction therapies remains desirable. As this requires multidrug regimens, the identification of synergizing agents may be key for efficacy and in preventing toxicity. In search for drugs that strongly synergize against KMT2A-rearranegd ALL, we first conducted high-throughput combinatorial drug screens in cell line models. As a result, we found that any possible 2-drug combination of venetoclax, ponatinib, and trametinib was highly synergistic in vitro. The drug synergy was confirmed in vivo in a cell line-derived xenograft (CDX) mouse model but could not be validated in patient-derived primary KMT2A-rearranged infant ALL samples in vitro. Yet, in patient-derived xenograft (PDX) mouse models, drug synergy did emerge at a comparable level as observed in our CDX model. Regrettably, none of the synergistic 2-drug combinations appeared sufficiently effective in preventing leukemia outgrowth in our PDX models, which likely requires combinations of >2 drugs. Hence, our results illustrate/signify that straightforward high-throughput combinatorial drug screening in leukemia cell lines is a valid approach to identify synergistic drug combinations that are verifiable in vivo in PDX mouse models without requiring validation in primary patient cells in vitro.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100230
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