bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–09–13
eighteen papers selected by
William Grey, University of York
  1. Rare Hematopoietic Stem Cells resilient to infection-induced stress sense yet withstand inflammation.
  2. Haematopoietic stem cell fitness mechanisms.
  3. Midbody inheritance predicts re-entry into quiescence, but not lineage potential, in mouse hematopoietic stem cells.
  4. Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
  5. CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.
  6. Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
  7. Patient-derived mesenchymal stromal cells establish an IL-6 axis that marks progression from smouldering to active multiple myeloma.
  8. LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.
  9. The lifelong transcriptomic landscape of human blood cells.
  10. Umbilical cord blood infusion enhances hematopoietic recovery and improves survival in elderly AML patients with chemotherapy-induced myelosuppression: a retrospective study.
  11. Ficoll-based isolation biases the profiling of immune cells and leukemic blasts in AML samples.
  12. Transcription factor 12 promotes acute myeloid leukemia cell survival by regulating mitochondrial function and ROS.
  13. The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.
  14. High-Content Imaging Workflow for Single-Cell Drug Response Profiling of Acute Myeloid Leukemia Subtypes.
  15. Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death.
  16. The proteomic architecture of clonal hematopoiesis: a systematic review of niche remodeling and multi-compartment predictors of malignant transformation.
  17. 4D spatiotemporal landscape of mitochondrial phenotypes across cellular states unlocked through representation learning.
  18. Partaker: deep-learning-based single-cell-resolution analysis of multi-dimensional, long-term, microfluidic-based time-lapse microscopy data.
  1. Blood. 2026 Sep 09. pii: blood.2025032368. [Epub ahead of print]
    Rare Hematopoietic Stem Cells resilient to infection-induced stress sense yet withstand inflammation.
    Christiana Georgiou, Qi Liu, Federica Bruno, Cera Mai, Floriane Simonne Tissot, Xuanxuan Fan, Sara Gonzalez Anton, Flora Birch, Debangana Mukhopadhyay, Sarah J Kinston, Shirom Chabra, Célia Sergi, Nick van Gastel, Ilaria Malanchi, Nicola K Wilson, Ken R Duffy, Constandina Pospori, Andrew M Blagborough, Berthold Gottgens, Tiago C Luis, Cristina Lo Celso.
      Hematopoietic stem cells (HSCs) sustain lifelong hematopoiesis as their progeny differentiate into all blood cell lineages. Homeostatic HSCs are mostly quiescent and only rarely divide, however their proliferation and differentiation rates can be modulated by external factors. Acute and chronic infections from a wide range of pathogens are known to challenge HSCs at the population level, being forced to respond to inflammation-mediated organismal demand to replenish the myeloid cell pool. However, less is known about the degree of heterogeneity in the HSCs' response to inflammation at the single cell level. Here, using a natural murine malaria model and an NHS-ester biotin dilution assay we identify two subsets of HSCs, BiotinLo and BiotinHi, with distinct proliferation kinetics. Using combined functional, single-cell transcriptomics and phenotypic analyses, we uncover that BiotinHi HSCs remain highly functional despite expressing strong interferon response signatures. These resilient HSCs are more poised to enter cell cycle than control HSCs, but do not divide. They maintain less active mitochondria and express higher levels of CD74 and MHC-II. Additionally, they express higher levels of integrin β2/CD18, which suggest they may have specific interactions with the bone marrow microenvironment. Similar patterns of NHS-ester biotin dilution were elicited by LPS and poly (I:C) challenges. These findings highlight previously unmeasured heterogeneity in the response of HSCs to acute infection-induced inflammation and demonstrate that a likely reserve pool of HSCs remains highly functional during Plasmodium infection not because cells are shielded, but because they maintain a stemness associated metabolic profile despite effectively sensing inflammation.
    DOI:  https://doi.org/10.1182/blood.2025032368
  2. Exp Hematol. 2026 Sep 07. pii: S0301-472X(26)00538-2. [Epub ahead of print] 105905
    Haematopoietic stem cell fitness mechanisms.
    Yavor Bozhilov, Hugo Vassort, Adam C Wilkinson.
      Haematopoietic stem cells (HSCs) are important for human health and clinical therapy. A heterogenous pool of HSCs sustain blood production through life by balancing self-renewal and multilineage differentiation. Aging is associated with a decline in the function of the HSC pool and haematopoietic perturbations. Additionally, aging correlates with clonal haematopoiesis, driven by the accumulation of genetic mutations in this long-lived cell population that can lead to altered cell function and ultimately to leukemic transformation. Alongside their natural role in sustaining haematopoiesis, healthy HSCs are also used clinically for their regenerative capacity in stem cell transplantation, where they reconstitute the entire adult blood system and can cure a range of blood disorders. Within these contexts, the term fitness is regularly used but often poorly defined. In this perspective, we summarise two distinct types of HSC fitness, clonal fitness and stem cell fitness. We go on to introduce mechanisms known to shape each and discuss the therapeutic implications for modulating HSC fitness mechanisms. TEASER ABSTRACT: This Perspective discusses two types of hematopoietic stem cell fitness, clonal fitness and stem cell fitness, and summarise mechanisms known to shape each and their therapeutic implications.
    Keywords:  Hematopoietic stem cell; clonal fitness; clonal hematopoiesis; stem cell fitness
    DOI:  https://doi.org/10.1016/j.exphem.2026.105905
  3. Exp Hematol. 2026 Sep 06. pii: S0301-472X(26)00537-0. [Epub ahead of print] 105904
    Midbody inheritance predicts re-entry into quiescence, but not lineage potential, in mouse hematopoietic stem cells.
    Tsuyoshi Fukushima, Arne Wehling, Ren Shimamoto, Shuhei Asada, Shunsuke Kawamura, Tomofusa Fukuyama, Susumu Goyama, Timm Schroeder, Toshio Kitamura, Yosuke Tanaka.
      Hematopoietic stem cells (HSCs) give rise to all blood cell lineages and possess long-term self-renewal potential. HSCs undergo symmetric division for their expansion and asymmetric division to generate one HSC and one progenitor cell which contribute to production of mature blood cells. The midbody is a structure which is formed in the center of the intercellular bridge during cytokinesis. However, the midbody is either asymmetrically inherited by one daughter cell or symmetrically released after cell division, whether these distinct patterns of midbody inheritance influence HSC fate remain poorly understood. In this study, we designed a fusion protein hmKO2 and MgcRacGAP which is a component of midbody. We then traced the midbody inheritance during cell division and the future cell fates of HSC daughters after division by time-lapse imaging. As a result, we found that the midbody release correlated with the delay of the time to the next division but not to the lineage potential of HSCs, indicating the possibility that midbody remnant plays some roles in cell cycle progression.
    Keywords:  Asymmetrical division; Hematopoietic Stem Cell; MgcRacGAP; Midbody
    DOI:  https://doi.org/10.1016/j.exphem.2026.105904
  4. Nat Commun. 2026 Aug 11. pii: 9611. [Epub ahead of print]17(1):
    Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
    Chen Song, Peng Yang, Yu Li, Tao Xia, Rui Li, Mengmeng Guo, Wenjun Li, Chenfeng Liu, Tiantian Jia, Yansheng Wang, Xunxia Bao, Qi Wang, Yuan Yao, Qian Dai, Huan Liu, Zongwei Li.
      Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.
    DOI:  https://doi.org/10.1038/s41467-026-76595-0
  5. Exp Hematol Oncol. 2026 Sep 07. pii: 90. [Epub ahead of print]15(1):
    CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.
    Xuemei Wang, Xiangjie Lin, Tianyi Chen, Yi Chen, Huafeng Wang, Yinghui Zhu.
      Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.
    Keywords:  Acute myeloid leukemia; CAR-T cell therapy; CD84; Redox homeostasis; Venetoclax resistance
    DOI:  https://doi.org/10.1186/s40164-026-00830-z
  6. Elife. 2026 Sep 11. pii: RP110919. [Epub ahead of print]15
    Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
    Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.
      Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of NINJ2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy, especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.
    Keywords:  Lamp1; NINJ2; cancer biology; ferritin; ferroptosis; human; lysosomal membrane permeabilities
    DOI:  https://doi.org/10.7554/eLife.110919
  7. Cytokine. 2026 Sep 10. pii: S1043-4666(26)00108-0. [Epub ahead of print]207 157213
    Patient-derived mesenchymal stromal cells establish an IL-6 axis that marks progression from smouldering to active multiple myeloma.
    Phoebe Elizabeth Blair, Tianyuan Chu, Andrew Robinson, Khalid Saja, Stuart Rushworth, Ralf Michael Zwacka, Andrea Mohr.
      IL-6 signalling in the bone marrow (BM) is compartmentalised. Different cell populations within the BM niche contribute distinct components of the IL-6 signalling network, yet how their roles change during myeloma progression has remained unclear. We examined how the respective contributions of mesenchymal stromal cells (MSCs) and primary multiple myeloma (MM) cells to the IL-6 signalling machinery change during disease progression. MSCs were identified as the principal source of IL-6, whereas MM cells secreted minimal IL-6 but were the primary source of soluble IL-6 receptor (sIL-6R). This functional interplay, with MSCs supplying the ligand and MM cells providing the soluble receptor, establishes a paracrine IL-6 trans-signalling axis. The contribution of MM cells to this axis increases significantly with disease stage: cells from patients with active MM secreted substantially greater quantities of sIL-6R than those from patients with smouldering disease, identifying sIL-6R as a marker of biologically active disease. This increase is mirrored by higher basal IL-6 secretion from MSCs in advanced disease, demonstrating augmentation of the IL-6 signalling pathway as disease progresses. Using Hyper-IL-6 and sgp130, we demonstrated that trans-signalling through gp130 is the dominant mechanism by which stromal-derived IL-6 protects MM cells from treatment-induced apoptosis, independent of membrane-bound IL-6R expression. Therefore, targeted inhibition of IL-6 trans-signalling with sgp130 could be used to suppress pathogenic effects in MM while preserving beneficial classical IL-6 signalling, offering a more precise and potentially safer alternative to total IL-6/IL-6R blockade. As disease progression increases trans-signalling through higher sIL-6R expression, early intervention in smouldering myeloma, before pathway amplification, may represent a more effective therapeutic strategy.
    Keywords:  IL-6; Mesenchymal stromal cell; Multiple myeloma; Trans-signalling; sIL-6R; sgp130
    DOI:  https://doi.org/10.1016/j.cyto.2026.157213
  8. Blood Sci. 2026 Sep;8(3): e00296
    LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.
    Mutian Cao, Lizhen Cong, Yifei He, Mingyue Hao, Yuanyi Ling, Wanting Li, Mingyue Zhang, Weiping Yuan, Yajing Chu.
      Acute myeloid leukemia (AML) is a group of genetically and clinically heterogeneous malignancies characterized by clonal expansion of immature myeloid progenitors and profound disruption of normal hematopoiesis. Emerging evidence suggests that alterations in cellular homeostasis shape cancer progression. However, the mechanisms underlying AML progression remain largely unclear. Here, we identify lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme of the Lands' cycle, as a critical regulator of AML progression. Analysis of public transcriptomic datasets and patient-derived CD34+ cells revealed robust LPCAT3 overexpression in AML and an association between high LPCAT3 levels and inferior overall AML patient survival. Suppression of LPCAT3 by shRNA or CRISPR-Cas9 in MOLM-13 and THP-1 cells markedly impaired proliferation, induced apoptosis, and caused G0/G1 cell-cycle arrest. Conversely, enforced overexpression promoted cell survival. In xenograft murine models, LPCAT3 depletion reduced leukemic burden. RNA-seq following LPCAT3 loss showed that genes differentially expressed were significantly enriched in granulocyte chemotaxis-related pathways, suggesting a role of LPCAT3 in modulation of leukemic differentiation programs and microenvironmental interactions. Collectively, these data established that LPCAT3 as a previously unrecognized mediator of AML cell fitness and as a potential therapeutic target.
    Keywords:  Acute myeloid leukemia; Apoptosis; Cell proliferation; Chemotaxis; Immune microenvironment; LPCAT3
    DOI:  https://doi.org/10.1097/BS9.0000000000000296
  9. Protein Cell. 2026 Sep 08. pii: pwag064. [Epub ahead of print]
    The lifelong transcriptomic landscape of human blood cells.
    Xiaowei Xie, Lianshuo Li, Fang Hong, Yang Lei, Qianqian Meng, Xueying Zhao, Xuemei Peng, Yaojin Huang, Aiming Pang, Changya Chen, Xin Gao, Ping Zhu, Tao Cheng.
      Single-cell technologies have transformed our view of normal and malignant hematopoiesis, yet a framework linking lifelong homeostatic hematopoiesis to hematological diseases in blood ecosystem remains incomplete. Here, we constructed a high-resolution landscape of the entire hematopoietic system by integrating transcriptomes of ∼1 million cells from 207 healthy samples spanning five developmental stages (fetal, neonatal, childhood, adult, elderly), and identified 96 blood cell clusters, including a VNN2-marked monocyte subset in the fetus and TSHZ2-marked T cell subsets exhibiting distinct age-dependent dynamics. We uncovered a reversal in hematopoietic stem cell/multipotent progenitor (HSC/MPP) stemness around childhood and a postnatal lymphoid bias shift from reduced early B/T lineage potential to enhanced natural killer (NK) cytotoxicity, coordinately orchestrated by intracellular transcription factor activity and intercellular interactions. Projecting 116 pan-malignancy samples (9 hematological malignancies) to our refined blood cell reference, we identified the upregulation of MYC and MHC II signaling as relatively conserved features correlating with poor prognosis, while hematopoiesis-related modules exhibited subtype-specific distributions with divergent clinical implications. Importantly, we developed a prognostic framework incorporating two core signatures shared across hematological malignancies and subtype-specific features. We further revealed an antagonism between inflammatory and cytotoxic programs across malignancies. Together, we established a panoramic landscape of the human hematopoietic system and elaborated its lifelong behaviors, in which a steady-state reference enabled the delineation of pathological hallmarks across hematological malignancies.
    Keywords:  atlas; development; hematopoiesis; malignancy
    DOI:  https://doi.org/10.1093/procel/pwag064
  10. Front Oncol. 2026 ;16 1867070
    Umbilical cord blood infusion enhances hematopoietic recovery and improves survival in elderly AML patients with chemotherapy-induced myelosuppression: a retrospective study.
    Yimin Zhou, Yuye Ren, Lan Zhang, Wenya Hu, Jiao Ma, Xiaomin Wang.
      Elderly AML (Acute Myeloid Leukemia) patients exhibit increased mortality owing to chemotherapy-induced myelosuppression. Umbilical cord blood (UCB) contains hematopoietic stem/progenitor cells and a spectrum of regenerative cytokines that actively promote hematopoietic regeneration. We investigated whether umbilical cord blood (UCB) infusion enhances hematopoietic recovery in elderly AML patients who experience chemotherapy-induced myelosuppression during post-chemotherapy supportive care.
    Methods: We retrospectively analyzed 95 elderly patients with AML in complete remission (CR1) who previously developed grade III-IV chemotherapy-induced myelosuppression. The control group (n=60) received standard supportive care, including granulocyte colony-stimulating factor (G-CSF), blood product transfusions, and antibiotic therapy. The experimental group (n = 35) underwent infusion of unrelated umbilical cord blood (UCB; CD34+ cells ≥2×106/kg) within 24 hours post - chemotherapy, along with standard supportive care.
    Results: Neutrophil recovery duration (≥1.0×109/L) was reduced in the UCB group (16 VS 23 days, P<0.01). Platelet recovery (≥50×109/L) was also shorter (13 days vs. 19 days, P<0.01), though hemoglobin recovery (≥70 g/L) did not differ significantly (18 days vs. 21 days, P>0.05). The incidence of grade III-IV infections decreased to 31.43% (vs. 55.00%, P<0.05), that of bleeding events decreased to 11.43% (vs. 33.33%, P<0.05), that of transfusion-related allergic reactions decreased to 17.14% (vs. 26.67%, P<0.05), and chemotherapy delay/reduction rates decreased to 14.29% (vs. 35.00%, P<0.05). The overall survival (OS) was significantly longer in the UCB group, and the 2-year relapse-free survival (RFS) was higher (P<0.05). The most common adverse events were transfusion-related (e.g., rash and transient fever). Graft-versus-host disease (GVHD) was not observed in the UCB group.These findings indicate that UCB infusion enhances hematopoietic recovery, reduces complications, and improves the survival of elderly patients with AML after chemotherapy, likely through the synergistic effects of CD34+ cells and cytokines.
    Keywords:  acute myeloid leukemia; elderly patients; post-chemotherapy myelosuppression; supportive therapy; umbilical cord blood infusion
    DOI:  https://doi.org/10.3389/fonc.2026.1867070
  11. Front Immunol. 2026 ;17 1920697
    Ficoll-based isolation biases the profiling of immune cells and leukemic blasts in AML samples.
    Bianca E Silva, Alison Daubry, Charline Faville, Adrien De Voeght, Jacques Foguenne, Mégane Jassin, Oswin Kwan, Leslie Correia Da Cruz, Gabriele Carriglio, Sébastien Charles, Alexandra Veloso, Frédéric Baron, Jo Caers, André Gothot, Grégory Ehx.
       Introduction: An increasing number of studies focus on anti-tumor immune responses. In acute myeloid leukemia (AML), blasts and immune cells, such as T cells, are frequently studied together in the same leukocyte sample. While hemolysis is the clinical standard for leukocyte isolation because it preserves the native leukocyte composition, Ficoll-based density gradient centrifugation is widely used in research and biobanking.
    Methods: Using hemolysis as a reference, we assessed whether Ficoll processing introduces biases into AML and immune cell profiling through analytical methods frequently applied in AML research.
    Results: Flow cytometry analyses showed that Ficoll systematically alters the composition of AML samples by enriching lymphocytes and AML blasts while depleting granulocytes. In RNA sequencing analysis, Ficoll isolation altered the expression of 1,136 genes, notably leading to an overestimation of the expression of leukemic stem cell gene sets. Immunogenomic deconvolution highlighted that Ficoll leads to an overestimation of CD8+ T-cell and monocyte abundances. Mutation calling from RNA-seq data revealed substantial discrepancies between methods, including failure to detect a clinically relevant DNMT3A R882 mutation in a Ficoll-processed sample. While Ficoll isolation had minimal impact on ex vivo AML blast expansion or chemotherapy response, it appeared to affect AML engraftment in NSG mice, possibly through the enrichment of T cells mediating graft-versus-host disease.
    Discussion: Together, these findings show that Ficoll isolation introduces bias in the cellular and molecular characterization of AML samples while having only a moderate impact on functional assays. We provide recommendations on which method to use depending on the investigator's objectives.
    Keywords:  AML; Ficoll; T cells; granulocytes; hemolysis; leukemic stem cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1920697
  12. Autoimmunity. 2026 Dec 31. 59(1): 2722938
    Transcription factor 12 promotes acute myeloid leukemia cell survival by regulating mitochondrial function and ROS.
    Nianxue Wang, Jianhong Xie, Ruya Zhang, Can Yang, Wei Ren, Liping Shu.
      Acute myeloid leukemia (AML) cells rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for energy, making mitochondrial function a promising therapeutic target. TCF12, a transcription factor belonging to the basic helix-loop-helix (bHLH) family, has been implicated in various cancers and is highly expressed in AML, where it may contribute to disease progression. However, the effects of TCF12 on AML progression and the underlying mechanisms remain unclear. This study aimed to elucidate the role of TCF12 in promoting AML cell survival and uncover the underlying mechanism. We found that TCF12 was highly expressed in AML and was associated with poor patient prognosis. Knockdown of TCF12 significantly inhibited AML cell growth, suppressed glycolysis, increased ROS accumulation, and induced mitochondrial dysfunction. Additionally, TCF12 was shown to promote EZH2 transcription, whereas its knockdown increased TXNIP expression, thereby inhibiting AML progression. In summary, TCF12 promotes AML progression by regulating EZH2-mediated suppression of TXNIP, thereby enhancing glycolysis, maintaining mitochondrial function, regulating ROS levels, and promoting cell survival, which underscores its potential as a therapeutic target.
    Keywords:  EZH2; TCF12; TXNIP; acute myeloid leukemia (AML); mitochondrial dysfunction
    DOI:  https://doi.org/10.1080/08916934.2026.2722938
  13. Blood. 2026 Sep 09. pii: blood.2026033874. [Epub ahead of print]
    The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.
    Thomas E Lew, Mark F van Delft, Luuk Heitink, Simon A Cobbold, Christine Anne White, Jason Alfredo Randall Bong, Philip Hittmeyer, Amelia H Zhu, Vineet Vaibhav, Jumana Yousef, Laura F Dagley, Christopher D Riffkin, Angela Georgiou, Adrienne Hilton, Allan Shuai Huang, Yin Yuan, Miles B Horton, Mark A Dawson, Andrew W Roberts, David Ching Siang Huang.
      The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria-ER contact sites (MERCS) that restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein-protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.
    DOI:  https://doi.org/10.1182/blood.2026033874
  14. SLAS Discov. 2026 Sep 09. pii: S2472-5552(26)00043-2. [Epub ahead of print] 100337
    High-Content Imaging Workflow for Single-Cell Drug Response Profiling of Acute Myeloid Leukemia Subtypes.
    Laura Isigkeit, Rekia Sinderwald, Jasmina Neumann, Ajlin Ismaili, Hong Yan, Sina Oppermann.
      Acute myeloid leukemia (AML) exhibits pronounced cellular heterogeneity, which contributes to variable therapeutic responses and limits the predictive power of conventional functional assays. While bulk viability measurements provide aggregated readouts, they fail to resolve phenotypic diversity and dynamic cellular states within heterogeneous populations. Here, we established a high-content fluorescence imaging workflow for quantitative drug response profiling (DRP) in AML at single-cell resolution. The assay integrates three non-toxic fluorescent dyes to capture features of nuclear morphology, mitochondrial function, and apoptosis. Automated high-content imaging combined with computational image analysis enables robust segmentation and extraction of phenotypic features across thousands of individual cells. Using a supervised machine learning approach, cells were classified into viable, apoptotic and dead states, enabling quantitative assessment of drug responses through population-normalized metrics. This approach allows direct integration of image-based data into downstream analysis workflows, facilitating the generation of functional dose-response curves and the determination of IC50 values and drug sensitivity scores (DSS) at single-cell resolution. The workflow was validated across seven AML cell lines, including models of acquired and mutation-driven resistance to BCL-2 inhibition. Image-based DRPs generated for venetoclax (VEN) showed strong concordance with established bulk measurements obtained using the ATP-based cell viability readout (CellTiterGlo®, CTG). Furthermore, screening of a 16-compound panel representing diverse mechanisms of action demonstrated robust agreement between image- and CTG-based drug response profiles while providing additional phenotypic information at single-cell resolution. Finally, the workflow was successfully transferred to primary AML samples. A pilot 31-compound drug screen identified BCL-2 inhibitors as the most active compounds, consistent with the patient's molecular profile. Together, this workflow establishes a scalable functional phenomics platform for high-resolution drug profiling and phenotypic stratification in AML. The integration of single-cell imaging with AI-based analysis provides a promising foundation for future functional precision oncology approaches, with potential applications in patient-specific DRP and combination therapy optimization.
    Keywords:  AI-based image analysis; acute myeloid leukemia; functional drug response profiling; machine learning analysis; single-cell phenomics
    DOI:  https://doi.org/10.1016/j.slasd.2026.100337
  15. Apoptosis. 2026 Sep 07. pii: 225. [Epub ahead of print]31(10):
    Activating a novel cell death pathway to target PI-resistant multiple myeloma and enhance immunogenic cell death.
    Xinyun Zhang, Zhiming Wang, Yilei Shi, Qi Li, Si Chen, Lexin He, Yali Chai, Hao Xu, Yuchen Zhang, Meifang Zhao, Wenzhuo Zhuang, Bingzong Li.
      Resistance to proteasome inhibitors (PIs) and inadequate engagement of anti-tumor immunity remain major barriers to effective treatment of multiple myeloma (MM). Here, we identified anwulignan, a bioactive natural product, as a translationally promising agent that retains activity in PI-resistant MM cells and promotes anti-myeloma immune responses. Anwulignan demonstrated potent cytotoxic activity against MM cells and exhibited strong synergy with proteasome inhibitors both in vitro and in vivo. In mouse MM models, anwulignan significantly suppressed tumor growth while maintaining favorable tolerability and safety profiles. Mechanistically, nucleophosmin 1 (NPM1) has been identified as a direct molecular target of anwulignan. Elevated NPM1 expression correlates with poor clinical outcomes in MM, and its inhibition by anwulignan induces cell cycle arrest and apoptosis. In addition to its tumor-intrinsic cytotoxic effects, anwulignan activated the caspase-1-dependent gasdermin D (GSDMD) pyroptosis pathway, thereby inducing immunogenic cell death. Genetic silencing of GSDMD markedly impaired anwulignan-mediated tumor suppression in vitro and in vivo, highlighting pyroptosis as a critical effector mechanism. In immunocompetent syngeneic MM models, anwulignan treatment increased bone marrow and splenic T-cell proportions and achieved superior tumor control compared with GSDMD-deficient tumors. Collectively, these findings establish anwulignan as a dual-function therapeutic that directly targets MM cell survival while simultaneously promoting anti-tumor immunity through pyroptosis-driven immunogenic cell death. This study provides a strong translational rationale for leveraging natural products as immune-engaging strategies to target drug-resistant multiple myeloma and improve therapeutic outcomes.
    Keywords:  Anwulignan; Immunogenic cell death; Multiple myeloma; Proteasome inhibitors; Pyroptosis
    DOI:  https://doi.org/10.1007/s10495-026-02426-8
  16. Front Med (Lausanne). 2026 ;13 1818220
    The proteomic architecture of clonal hematopoiesis: a systematic review of niche remodeling and multi-compartment predictors of malignant transformation.
    Jana H Husein, Rasha M Khayata, Aisha Jahangir, Ghaith K Mansour, Ahmed W Hajjar, Muhammad Raihan Sajid.
       Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor to myeloid malignancies, yet the functional proteomic landscape that governs clonal fitness and microenvironmental remodeling remains poorly understood. This systematic review consolidates high-resolution proteomic evidence to map the transition from stable CHIP to overt malignancy.
    Methods: Following PRISMA 2020 guidelines, we analyzed 15 high-quality studies (selected from 83 initial records) published between 2015 and 2025. The review integrates data from diverse proteomic platforms-including DIA-MS, TMT labeling, and Olink high-plex panels across hematopoietic stem/progenitor cells (HSPCs), the bone marrow niche, and blood. Risk of bias was rigorously assessed using ROBINS-E, QUIPS, and SYRCLE frameworks.
    Results: Synthesis of the evidence reveals a profound "Genotype-Proteotype Gap," characterized by a low median mRNA-protein correlation (0.30) in aging stem cells. Clonal expansion is associated with a non-linear "functional niche failure" exceeding a 5% VAF threshold, marked by the emergence of inflammatory mesenchymal stromal cells (iMSCs) expressing IL-1R1 and CD44. Systemically, proteomic risk scores utilizing markers such as F7, BIN2, and CXCL11 can predict incident myeloid neoplasms over a decade before clinical diagnosis. Evidence strength varies substantially, with high-strength support for plasma predictive signatures and preliminary-to-moderate support for mechanistic findings from smaller cohorts.
    Conclusion: This systematic review identifies that malignant progression is dictated by a qualitative proteomic "switch" and structural niche reorganization. However, causal relationships remain to be definitively established. We identify a critical "Spatial Architecture Gap" in current research, highlighting the need for spatial proteomic platforms to map the physical "handshake" between mutant clones and their inflammatory environment to enable early clinical interception.
    Keywords:  biomarker discovery; bone marrow microenvironment; clonal hematopoiesis; inflammaging; malignant transformation; proteomics
    DOI:  https://doi.org/10.3389/fmed.2026.1818220
  17. Cell. 2026 Sep 10. pii: S0092-8674(26)01001-9. [Epub ahead of print]
    4D spatiotemporal landscape of mitochondrial phenotypes across cellular states unlocked through representation learning.
    Dhruv Agarwal, Zichen Wang, Eric Arkfeld, Andre Modolo, Parth Natekar, Hiroyuki Hakozaki, Mehul Arora, Gillian McMahon, Siddharth Nahar, Manav Doshi, Johannes Schöneberg.
      Mitochondria are four-dimensional (4D: x, y, z, and time) organelles essential for cellular function. Characterizing their 4D phenotypic landscape across diverse cellular states requires both 4D imaging and analytical frameworks. We present MitoSpace, a self-supervised deep learning model trained without labels on terabytes of single-cell lattice light-sheet microscopy data of mitochondria under mechanistically distinct perturbations. MitoSpace learns latent representations that outperform predefined features in drug classification and capture interpretable variation in mitochondrial morphology and dynamics. Regression probes predict mitochondrial membrane potential from the learned representations (R2 = 0.91), establishing a quantitative mapping between form and function at the single-cell level. MitoSpace also generalizes zero-shot to unseen perturbations and human lung organoids. Dimensionality ablation reveals that representation quality improves monotonically from 2D to 3D to 4D, demonstrating the importance of volumetric and temporal information. The model, dataset, and interactive explorer are publicly available, providing a foundation for 4D phenotypic screening.
    Keywords:  contrastive learning; drug mechanism of action; foundation model; high-content phenotypic screening; lattice light-sheet microscopy; live-cell 4D imaging; mitochondria; mitochondrial dynamics; mitochondrial membrane potential; self-supervised learning
    DOI:  https://doi.org/10.1016/j.cell.2026.08.028
  18. Bioinformatics. 2026 Sep 10. pii: btag675. [Epub ahead of print]
    Partaker: deep-learning-based single-cell-resolution analysis of multi-dimensional, long-term, microfluidic-based time-lapse microscopy data.
    Henrique H Libutti-NúÑez, Bukola A Akindipe, Hamed Rastaghi, Nona Hashemi, Samuel M D Oliveira.
       MOTIVATION: Deep-learning segmentation models for microbial time-lapse fluorescence microscopy already exist, but they are often difficult to use consistently across experiments and are not packaged with unified workflows for combining models, quantifying multi-channel fluorescence, and scaling analyses to large microfluidic imaging datasets.
    RESULTS: To address these challenges, we developed Partaker, an easy-to-use Python-based graphical tool for deep-learning segmentation, multi-channel fluorescence quantification, and morphological analysis of microbial cells over time. Partaker supports extensible model integration, efficient handling of large imaging datasets, and interactive visualization, enabling time-resolved analysis of population fluorescence distributions from per-cell measurements. We demonstrate performance using a two-strain validation experiment (housekeeping and inducible) and show robust recovery of population-level fluorescence dynamics with single-cell resolution.
    AVAILABILITY AND IMPLEMENTATION: Partaker is implemented in Python and is available on GitHub (https://github.com/SamOliveiraLab/partaker). A versioned release of the software is archived on Zenodo (https://doi.org/10.5281/zenodo.18844425). Documentation, example datasets, and installation instructions are provided in the repository.
    DOI:  https://doi.org/10.1093/bioinformatics/btag675
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