bims-scepro 2026-08-02 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–08–02
eighteen papers selected by
William Grey, University of York

Chromatin Accessibility Shapes Developmental-Specific Lineage Plasticity in Hematopoiesis.
Single cell multi-omics enables high-resolution identification and functional purification of human acute myeloid leukemia stem cells.
Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance.
Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation.
Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
Targeting cellular senescence alleviates bone marrow aging.
Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.
Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.
Inference of secreted protein signaling activities in intercellular communication.
Golgi organization regulates stem cell function in the small intestine.
An AI-enabled structural atlas decodes kinase specificity across the human proteome.
Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.
Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma.
Cross-Correction in HSC Gene Therapy for Metachromatic Leukodystrophy.
Activating RARβ to overcome immunomodulatory drug resistance in t(4;14) human myeloma.
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
Proteostatic defect drives biophysical remodeling that triggers cell competition.
FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.

Blood Adv. 2026 Jul 30. pii: bloodadvances.2026019909. [Epub ahead of print]

Chromatin Accessibility Shapes Developmental-Specific Lineage Plasticity in Hematopoiesis.

Sara Palo, Keiki Nagaharu, Mikael N E Sommarin, Rasmus Olofzon, Virginia Turati, Shamit Soneji, Göran Karlsson, Charlotta Böiers.

Cell differentiation is governed by dynamic changes in chromatin accessibility, and its dysregulation underlies multiple disease states. Prior to birth, development of the hematopoietic system constitutes a period of broad differentiation potential, with certain immune cells arising exclusively during ontogeny. While age is known to affect lineage bias, the underlying molecular differences driving lineage preference in fetal and adult human hematopoietic stem and progenitor cells (HSPCs) remain unclear. Through single-cell cultures of hematopoietic stem cells (HSCs), we observed that fetal cells frequently generate mixed-lineage colonies, whereas adult HSCs are biased towards myeloid output. To investigate how these lineage preferences were encoded at the chromatin level, we performed single-cell ATAC-sequencing on first-trimester HSPCs. While adult HSCs showed enrichment of lineage-specific transcription factor motifs, fetal cells lacked such enrichment, consistent with their broader differentiation potential. We additionally uncovered a developmental-specific plasticity in fetal lymphoid progenitors, manifested as a hybrid lympho-myeloid chromatin program not present in adult progenitors. Additionally, the motif and putative regulatory elements for PAX5, a master regulator of B cell development, showed markedly reduced accessibility in fetal cells, supporting a more plastic and less restricted lymphoid state. This enhanced embryonic lineage plasticity may underlie the prenatal susceptibility to mutational drivers of acute lymphoblastic leukemia.

DOI: https://doi.org/10.1182/bloodadvances.2026019909
bioRxiv. 2026 Jul 13. pii: 2026.07.12.737989. [Epub ahead of print]

Single cell multi-omics enables high-resolution identification and functional purification of human acute myeloid leukemia stem cells.

Asiri Ediriwickrema, Yusuke Nakauchi, Thomas Köhnke, Amy C Fan, Xiaoyi Hu, Brooks A Benard, Daiki Karigane, Miles H Linde, Aaron M Newman, Andrew J Gentles, Ravindra Majeti.

In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.
Key Points: Single cell multi-omics identifies human AML LSCs at high resolution. HOPX and SOCS2 co-expression (hrLSC2) defines a prognostic gene signature in de novo acute myeloid leukemia. hrLSC2 marks an AML subpopulation (iLSCs) with a distinct immunophenotype.iLSCs can be purified using flow cytometry and are significantly enriched for LSCs.

DOI: https://doi.org/10.64898/2026.07.12.737989
Leukemia. 2026 Jul 27.

Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance.

Alison E Meyer, Katelyn E Heimbruch, Kirthi Pulakanti, Cary Stelloh, Nataly Cruz-Rodriguez, Josiah Murray, Dandan Wang, Lisa Latzko, Sebastian Vosberg, Philipp A Greif, Lucio H Castilla, John A Pulikkan, Subramaniam Malarkannan, Sridhar Rao.

Core binding factor (CBF) acute myeloid leukemias typically harbor the translocations t(8;21) or inv(16). As cohesin mutations are less commonly observed with inv(16) than with t(8;21), we hypothesized that they may negatively impact inv(16)-driven AML. Using a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3, we paradoxically found that inv(16); Smc3Δ/+ mice have a reduced leukemic latency compared to inv(16); Smc3+/+ mice, disproving our initial hypothesis and instead suggesting a role for cohesin loss in enhancing inv(16)-driven disease. Consistent with the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16); Smc3Δ/+ hematopoietic stem and progenitor cells (HSPCs) prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. Through scRNA-seq on pre-leukemic HSPCs, we observe an increase in Fli1 expression and enhanced Fli1 target expression in ST-HSCs. We further show that Fli1 is essential for the maintenance stage of inv(16); Smc3Δ/+ AML. Our data demonstrate a role for cohesin loss in enhancing the aggressiveness of inv(16)-driven AML and identify Fli1 as a previously unrecognized therapeutic vulnerability in cohesin-mutated AML.

DOI: https://doi.org/10.1038/s41375-026-03070-6
Blood. 2026 Jul 28. pii: blood.2026033834. [Epub ahead of print]

Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation.

Elia Colin, Dror Brook, Jonathan Izraeli, Oren Milman, Aviezer Lifshitz, Tal Bacharach, Noa Chapal-Ilani, Liran I Shlush, Amos Tanay.

Hematopoietic stem and progenitor cells (HSPCs) balance self-renewal with on-demand differentiation of blood lineages. Modern bone marrow atlases specify static transcriptional states, but not HSPC dynamics, which are only partly understood, particularly in humans. Here, we introduce cHSPCTrack (clonal HSPC tracker), an in vitro framework for serially tracking clonal differentiation and fate acquisition from human HSPCs extracted from circulation. By following thousands of single-cell-derived clones stimulated by different cytokine combinations, cHSPCTrack reconstructs the balance between stochasticity and directed differentiation in human HSPCs. Single HSPCs stochastically yield multiple lineages under a uniform cytokine environment, with stimulatory inputs modulating differentiation probabilities by introducing biases toward preferred fates. In parallel, differentiation rates vary stochastically across and within clones. Clonal memory stabilizes the induction of a few genes per clone over otherwise archetypical differentiation trajectories. Within clones, multiple fates can interact with each other, as shown for clones mixing basophils, eosinophils, and mast cells with other fates. cHSPCTrack opens avenues for understanding hematopoietic clonal dynamics in health and disease.

DOI: https://doi.org/10.1182/blood.2026033834
bioRxiv. 2026 Jul 13. pii: 2026.07.10.737821. [Epub ahead of print]

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.

Matthew T Villaume, Haley E Ramsey, Valeria Impedovo, Michael Davidson, Maria P Arrate, Anand K Singh, Yujin Lee, Anna Skwarska, Yara F Almadani, Natalia Baran, Sovira Chaudhry, Benjamin J Reisman, Eden G TenBarge, Ming Jiang, Sarah Olmstead, Agnieszka E Gorska, Zhiguo Zhao, Andrew J Monteith, Peter M Grace, Brian O Bachmann, Marina Konopleva, Stefano Tiziani, Michael R Savona.

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

DOI: https://doi.org/10.64898/2026.07.10.737821
bioRxiv. 2026 Jul 17. pii: 2026.07.16.736849. [Epub ahead of print]

Targeting cellular senescence alleviates bone marrow aging.

Bowen Yan, Jin Han, Yang Yang, Peiyi Zhang, Jason O Brant, Jianhui Chang, Ha-Neui Kim, Maria Almeida, Prabhjot Kaur, Qingchen Yuan, Marco Demaria, Kalyanee Shirlekar, Jennifer Elisseeff, Guangrong Zheng, Ying Liang, Daohong Zhou, Olga A Guryanova.

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

DOI: https://doi.org/10.64898/2026.07.16.736849
bioRxiv. 2026 Jul 14. pii: 2026.07.13.737885. [Epub ahead of print]

Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.

Anagha Deshpande, Cho-Ying Chiang, Marlenne Perales, Neha Niranjan, Neelam Sinha, Darren Finlay, Alexandra Stevens, Emily Zahn, Benjamin A Garcia, Irmela Jeremias, Mark Wunderlich, Kristen Jensen-Pergakes, Akshata Udyavar, Amy Carr, Andrew R Nager, Yanling Yang, Rabi Murad, Courtney Jones, Shawn O'Connell, Thomas Paul, Kristiina Vuori, Aniruddha J Deshpande.

Transcriptional condensates anchored by chromatin readers are increasingly recognized as organizing hubs for gene expression, but how their assembly and stability are regulated remains poorly understood. Here, we identify an acetylation-dependent feed-forward circuit that controls the integrity of the Super Elongation Complex (SEC), a key driver of transcriptional elongation. We show that the SAGA histone acetyltransferase catalytic subunits KAT2A/KAT2B license acetylation of both histone H3 lysine 9 (H3K9ac) and SEC components themselves, including ENL, AFF1, and AFF3. Loss of this dual acetylation activity, achieved via a cereblon-recruiting PROTAC (GSK983/GSK699), displaces the chromatin reader ENL from target loci, dissolves ENL-anchored transcriptional condensates, and disrupts SEC-dependent transcriptional output - linking histone and non-histone acetylation to the physical integrity of a core transcriptional machine. Using genome-scale dependency data, we show that the SAGA complex is a selective chromatin dependency in acute myeloid leukemia (AML) AML and hematological malignancies and disrupting this feed-forward transcriptional circuit in AML demonstrates subtype independent antileukemia effects. KAT2A/B degradation drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations, with H3K9ac loss concentrated asymmetrically at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. Together, these findings define an acetylation-dependent circuit governing SEC integrity and establish KAT2A/B degradation as a mechanism-based, pan-AML therapeutic strategy, with implications for transcriptional condensate regulation beyond leukemia.
HIGHLIGHTS: The SAGA complex is a selectively essential chromatin dependency across hematological malignancies and particularly in AMLKAT2A/B degradation drives broad anti-leukemic activity across genetically diverse AML subtypes including chemo-refractory diseaseKAT2A/B degradation depletes H3K9ac at AML oncogene loci and dismantles ENL-anchored condensatesKAT2A/B licenses regulation of super elongation complex acetylation and ENL interaction with SEC complex components.

DOI: https://doi.org/10.64898/2026.07.13.737885
Leukemia. 2026 Jul 29.

Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.

Long Shen, Jinting Fan, Ning Wang, Zihao Wang, Yang Yang, Chenghua Xu, Siyi Liu, Dong Zhang, Youyang Fang, Bingqian Chu, Tingting Zhang, Wenshuo Liu, Lichun Kang, Zhiwei Zhou, Mingming Niu, Hong Wang.

Resistance to FLT3 inhibitors remains a major limitation in the treatment of FLT3-mutated acute myeloid leukemia (AML). Canonically, ERK is considered the predominant MAPK effector downstream of FLT3 signaling. However, pharmacologic inhibition of MEK/ERK provides limited clinical benefit once resistance develops, suggesting that alternative signaling dependencies may emerge under therapeutic pressure. Using an unbiased kinome-wide CRISPR-Cas9 screen in gilteritinib-resistant AML cells, we identified MAPK14 (encoding p38α), rather than MAPK3/MAPK1 (encoding ERK1/2), as a prominent context-dependent dependency associated with the resistant state. Genetic impairment or pharmacologic inhibition of p38 enhanced gilteritinib sensitivity and synergized with FLT3 inhibition to suppress leukemic growth. Mechanistically, resistant cells exhibited adaptor-mediated rewiring of FLT3 signaling, in which p46-SHC1 supported an FLT3-associated MKK3/6-p38 signaling module despite FLT3 inhibition, thereby sustaining downstream programs including MYC expression. Consistent with its role as a stress-responsive kinase, p38 supports leukemic cell survival under prolonged drug exposure. Together, these findings define a non-canonical MAPK signaling state associated with FLT3 inhibitor resistance, provide a mechanistic explanation for the limited efficacy of MEK/ERK-directed therapies in the resistant setting, and offer a rationale for combination strategies targeting stress-adaptive pathways to improve the durability of FLT3-directed therapy in AML.

DOI: https://doi.org/10.1038/s41375-026-03079-x
Nat Methods. 2026 Jul 30.

Inference of secreted protein signaling activities in intercellular communication.

Beibei Ru, Lanqi Gong, Emily Yang, Seongyong Park, George Zaki, Kenneth Aldape, Lalage Wakefield, Peng Jiang.

The human genome encodes ~1,900 secreted proteins, many of which mediate intercellular communication. Secreted proteins do not act cell-autonomously, limiting systematic approaches to characterize their functions. Here we introduce SecAct (Secreted Activity, https://secact.ccr.cancer.gov ), a computational framework that infers the signaling activities of 1,170 human secreted proteins from spatial, single-cell and bulk transcriptomic data. The inference model harnesses precomputed intercellular signaling signatures trained on 1,258 spatial transcriptomics samples spanning 37 cancer types. Transcriptomics data from antisecreted protein therapies validate SecAct's accuracy in predicting the repression of secreted protein activity following treatment. For spatial and single-cell transcriptomics data, SecAct provides interactive modules for analyzing secreted protein-mediated cell-cell communication. Applying SecAct to 54 cancer immunotherapy cohorts comprising 5,174 patients, we identified secreted proteins associated with tumor immunity. In vivo experiments validated lymphocyte antigen 86 (LY86), whose function in cancer was previously unknown, as an antitumor regulator.

DOI: https://doi.org/10.1038/s41592-026-03172-0
Nat Commun. 2026 Jul 29. pii: 7606. [Epub ahead of print]17(1):

Golgi organization regulates stem cell function in the small intestine.

Ilya Belevich, Lucas Porcile, Agustin Sola-Carvajal, David Grommisch, Karl Annusvar, Paul Heinz, Srustidhar Das, Anna T Webb, Simon Andersson, Nalle Pentinmikko, Eduardo J Villablanca, James R Goldenring, Maria Kasper, Eija Jokitalo, Robert J Coffey, Pekka Katajisto, Sandra Scharaw.

Cell-to-cell signaling between niche and stem cells regulates tissue renewal. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. ISCs orient their Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks. Stem cells with multiple lateral Golgi transport stem cell receptors with a higher efficiency than cells with one single Golgi. The lateral Golgi orientation and enhanced receptor transport requires A-kinase anchor protein 9 (Akap9), and is necessary for normal renewal capacity. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal a stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue renewal, which is compromised in the aged epithelium.

DOI: https://doi.org/10.1038/s41467-026-75679-1
Nat Biotechnol. 2026 Jul 29.

An AI-enabled structural atlas decodes kinase specificity across the human proteome.

David R Vanderwall, Edward L Huttlin, Julian Mintseris, Tomer M Yaron-Barir, Jared L Johnson, Kevin D Dong, Alex J Bott, Yuchen He, Christina B Schroeter, Geordon A Frere, Mohamed Uduman, Harin Lee, Sean Landry, Sean A Beausoleil, Joao A Paulo, Lewis C Cantley, Steven P Gygi.

Of the 1.8 million serine/threonine/tyrosine residues in the human proteome, only 6% bear experimental validation of phosphorylation, and only 5% of these have been mapped to a kinase. Here we present KinoPlex, a computational framework that integrates predicted protein structures and kinase recognition motifs to assign phosphorylation potential and kinase specificity to all serine/threonine/tyrosine residues. Using ~20,000 AlphaFold models and positive-unlabeled transfer learning, we identified ~567,000 residues as structurally phospho-competent. We intersected these with kinase position-specific scoring matrices to quantify motif specificity, yielding ~250,000 high-confidence candidates with sequence recognition potential and optimal structural presentation. The structural atlas uncovered fundamental organizing principles guiding kinase substrate recognition and dynamics of phosphorylation, including a phenomenon we call sequence-structure selective coupling, whereby kinases achieve specificity through structural scarcity of their preferred motif (negative-selecting kinases) or promiscuity through its structural accessibility (positive-selecting kinases), rather than by motif discrimination alone. Deep phosphoproteomics in K562 cells validates KinoPlex predictions and kinase enrichment capacities.

DOI: https://doi.org/10.1038/s41587-026-03239-5
Leukemia. 2026 Jul 31.

Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.

Chenxi Liao, Jin Wen, Xiao Ma, Nan Wang, Ying Chen, Lei Li, Lingbo Liu, Danyue Peng.

Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.

DOI: https://doi.org/10.1038/s41375-026-03053-7
Oncogene. 2026 Jul 25.

Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma.

Sireesh Kumar Teertam, Mithalesh K Singh, Sarah Altameemi, Sonia Gude, Sushmita Roy, Ryan N Rossman, Michael A Newton, Daniel D Bennett, Nihal Ahmad, Xiaodong Cheng, Vijayasaradhi Setaluri.

Progression of cutaneous primary melanoma that arises from melanocytes leads to lethal metastatic disease. Molecular mechanisms that control the growth of primary melanoma in the skin and promote progression are not fully understood. Previously we showed that RAP guanine exchange factors EPAC1/2 (Exchange Proteins Activated by cyclic AMP) promote the growth of primary melanoma and loss of dependency on EPACs is associated with metastatic progression. In this study, we show that EPACs are activated during malignant transformation of melanocytes, and chemical inhibition or genetic deletion of EPAC inhibits melanomagenesis in Braf/Pten mice. Low expression of EPAC mRNA and its effector RAP1-GTP protein in primary melanoma correlate with better recurrence-free survival. RNAseq analysis of matched primary and metastatic melanoma cells treated with an EPAC inhibitor showed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC signaling. We also show that EPACs promote melanoma growth by regulating redox homeostasis and mitochondrial ROS through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of redox regulator TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms that melanoma cells employ to bypass EPAC dependency is a potential therapeutic approach.

DOI: https://doi.org/10.1038/s41388-026-03895-6
N Engl J Med. 2026 Jul 30. 395(5): 508-511

Cross-Correction in HSC Gene Therapy for Metachromatic Leukodystrophy.

Vasco Meneghini, Valeria Calbi, Filippo Casalini, Elisabeth Mangiameli, Francesco Morena, Marco Piccoli, Ilaria Laface, Ilaria Rossomanno, Francesca Ornaghi, Andrea Ghiroldi, Paola M V Rancoita, Francesca Fumagalli, Sabata Martino, Luigi Anastasia, Luigi Naldini, Alessandro Aiuti, Angela Gritti.

DOI: https://doi.org/10.1056/NEJMc2505002
Leukemia. 2026 Jul 30.

Activating RARβ to overcome immunomodulatory drug resistance in t(4;14) human myeloma.

Ling Zhong, Qiang Wang, Miao Xian, Jianfei Qian, Chuanchao Zhang, Wei Wu, Qi Guo, Yufei Zhang, Rui Duan, Youli Zu, Sunil Mathur, Robert Z Orlowski, Fenghuang Zhan, Qing Yi.

The t(4;14) translocation is a high-risk cytogenetic abnormality in multiple myeloma (MM) that results in overexpression of fibroblast growth factor receptor 3 (FGFR3) and enhanced MM proliferation, leading to poor prognosis. Herein, we carried out a high-throughput screen on 1855 Food and Drug Administration (FDA)-approved pharmaceuticals and identified all-trans retinoic acid (ATRA), which alone has no anti-MM effect, as a potent drug that enhances the cytotoxic effects of immunomodulatory drugs (IMiDs) in t(4;14) MM cells. Mechanistically, ATRA activates retinoic acid receptor β (RARβ), which then binds to retinoic acid response elements in the FGFR3 promoter. IMiDs enhanced nuclear translocation of histone deacetylase (HDAC)-5 and 3 by reducing HDAC5 Ser498 phosphorylation levels. RARβ, HDAC5 and HDAC3 formed a co-repressor complex that reduced chromatin accessibility and H3K27 acetylation in FGFR3 promoter, FGFR3 expression, and suppressed phosphoinositide 3-kinase/AKT signaling pathways, leading to more MM cell death. Similarly, CD2314, a selective RARβ agonist, sensitized and resensitized t(4;14) MM cells to IMiDs in vitro and in vivo. Thus, these findings underscore the therapeutic potential of ATRA and RARβ agonists in enhancing the efficacy of IMiD-based treatments for t(4;14) MM and offer a promising strategy to overcome IMiD resistance and improve outcomes in this high-risk subgroup.

DOI: https://doi.org/10.1038/s41375-026-03078-y
Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2
iScience. 2026 Aug 21. 29(8): 116804

Proteostatic defect drives biophysical remodeling that triggers cell competition.

Wonjae Song, Mai Yukitake, Kei Kozawa, Nanami Sato, Jiaying Wen, Zehao Dai, Susumu Ishikawa, Akifumi Shiomi, Hirofumi Shintaku, Seiichiro Ishihara, Hisashi Haga, Yasuyuki Fujita.

  Cell competition is a fundamental tissue-surveillance process in which less-fit "loser" cells are actively eliminated by "winner" neighbors. Here, we establish a mammalian epithelial model of ribosomal protein insufficiency using Madin-Darby canine kidney (MDCK) cells with tetracycline-inducible shRNA targeting ribosomal protein large subunit 24 (Rpl24). When Rpl24-knockdown cells are co-cultured with normal cells, Rpl24-knockdown cells undergo apoptosis through cell competition with surrounding normal cells. Rpl24 knockdown disrupts protein homeostasis, leading to cytoplasmixc protein aggregates. The chemical chaperone 4-phenylbutyric acid (4-PBA) diminishes aggregate accumulation and markedly reduces competitive cell death. Proteostasis disruption also remodels cellular biophysics; Rpl24-knockdown cells exhibit lower homeostatic density, increased cell area, and reduced cell-surface tension. Importantly, these biophysical alterations are reversed by 4-PBA. Together, our findings reveal that ribosomal protein insufficiency links proteostatic stress to biophysical "loser" traits, establishing proteostasis-dependent biophysical remodeling as a key determinant of competitive cell elimination.

Keywords:  Ribosomal Protein Rpl24; apoptosis; cell competition; cellular biophysical alterations; mammalian cell culture; p53; proteostasis

DOI:  https://doi.org/10.1016/j.isci.2026.116804
bioRxiv. 2026 Jul 15. pii: 2026.07.14.738455. [Epub ahead of print]

FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.

Xiaorong Gu, Sudipta Biswas, Zeinab Albadry M Zahran, Songa Bae, Ramesh Balusu, Jaroslaw P Maciejewski, Babal K Jha, Yogen Saunthararajah.

  Internal-tandem-duplication of the receptor tyrosine kinase FLT3 (FLT3-ITD) generates ligand-independent signaling and is highly recurrent in acute myeloid leukemias (AMLs). One way signaling pathways can quickly influence cell fates is by phosphorylating key fate-determining proteins to trigger their proteolysis. We investigated the master transcription factor (MTF) driver of granulo-monocytic lineage-fates, CEBPA, for regulation by this mechanism because we found high CEBPA mRNA but little CEBPA protein in FLT3-ITD versus FLT3-wildtype AML cells, and inhibiting FLT3-ITD signaling with tyrosine kinase inhibitors (TKI) rapidly rescued CEBPA protein. Mass spectrometry analyses of CEBPA and its interactome demonstrated prominent interactions with major ubiquitin-proteosome pathway (UPP) components UHRF1 and USP7. TKI treatments decreased CEBPA and USP7 phosphorylations at serine 21 and serine 18 respectively alongside shifts in CEBPA interactions from degradative ubiquitin-ligase UHRF1 toward protective deubiquitinase USP7. The rescued CEBPA activated granulocytic-differentiation. Supporting that the serine-phosphorylations were 'phospho-degrons', UPP-inhibitors (bortezomib, MG132) increased phosphorylated and total CEBPA and USP7. The MTF regulator of apoptosis p53 is a known USP7 client, therefore, we also evaluated p53 status: TKIs and UPP-inhibitors stabilized USP7 and p53, triggering apoptosis in addition to granulocytic-differentiation specifically in FLT3-ITD but not FLT3-wildtype AML cells. UPP-inhibitors produced these consequences in TKI-resistant FLT3-ITD AML cells also. These data predicted genetic loss-of-function to CEBPA or TP53 is redundant in the FLT3-ITD context, borne out by mutual exclusivity of the mutations in clinical series. In summary, FLT3-ITD signals for CEBPA and p53 proteolysis to block lineage-maturation and apoptosis, positioning UPP-inhibitors as therapeutic candidates acting downstream of TKIs.

Keywords:  CEBPA; FLT3-ITD; USP7; acute myeloid leukemia; chemotherapy-resistance; p53; ubiquitin-proteosome pathway

DOI:  https://doi.org/10.64898/2026.07.14.738455