bims-scepro 2026-09-06 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–09–06
nineteen papers selected by
William Grey, University of York

Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia.
Csnk1a1 E98 mutations rewire signaling and metabolism in del(5q) myelodysplastic neoplasms.
Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.
The evolving role of umbilical cord blood in transplantation, immunotherapy, and regenerative medicine: a brief contemporary review by the ISCT lab practices committee.
AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.
Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.
KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.
Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.
A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.
XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.
CXXC1-dependent IRF4 activity promotes myeloma cell fitness and sustains lenalidomide resistance.
A single-amino-acid cleavage controls global mitochondrial complex integrity.
A single-cell atlas of multiple myeloma defines malignant archetypes and proliferative states.
MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
Spatial profiling identifies a distinct and topographically-defined tumor microenvironment that emerges during multiple myeloma evolution.
Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
Computational and Statistical Framework for Quantitative Proteomics Analysis.
Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.
Vitamin C promotes differentiation of stress-specific erythroid progenitors in stress erythropoiesis.

Leukemia. 2026 Sep 04.

Functional characterization of snoRNA-derived RNA (sdRNA) expression in healthy hematopoiesis and acute myeloid leukemia.

Rafael Zinz, Christian Rohde, Cornelius Pauli, Fengbiao Zhou, Azmal Ali Syed, Daniel Heid, Viral Shah, Niklas Alexander Wahl, Adrija Ray, Simon Renders, Laura Werner, Sandra Förmer, Carl Ahrens, Claudia Baldus, Martin Bornhäuser, Christoph Röllig, Hubert Serve, Tim Sauer, Jeroen Krijgsveld, Carsten Müller-Tidow, Maximilian Felix Blank.

SnoRNAs are highly expressed in AML and have implications in leukemogenesis and leukemic maintenance. SnoRNAs can be further processed into snoRNA-derived RNAs (sdRNAs). The role of sdRNAs in AML and healthy hematopoiesis remains largely elusive. We characterized sdRNA and snoRNA levels in hematopoietic stem and progenitor cells (HSPCs), healthy WBCs, and 159 intensively treated AML patient samples at initial diagnosis. HSPCs, healthy WBCs, and AML blasts could be differentiated by their sdRNA expression pattern in a cell-type-specific manner. In AML, high sd3'-RNA/snoRNA-host gene ratios were associated with an inverse patient outcome. Particularly, in NPM1-mutated patients with favorable risk stratification and good initial therapy response, high sd3'-RNA ratios identified a subgroup with inferior outcome. High sd3'-RNA ratios were associated with altered oncogenic, inflammatory, and immune response signaling. Forced expression of single sdRNAs, such as sd3'-SNORD78, sd3'-SNORD76, and sd5'-SNORD93, enhanced clonogenic potential in AML and drove sdRNA-specific gene expression signatures in both AML and healthy HSPCs. Exemplarily, we propose and characterize NUDT21, an important regulator of alternative polyadenylation and oncogenic gene expression, as a downstream target of sd3'-SNORD78 in AML. Our data introduce sdRNAs as standalone regulatory effector molecules in healthy hematopoiesis and AML.

DOI: https://doi.org/10.1038/s41375-026-03120-z
Leukemia. 2026 Sep 03.

Csnk1a1 E98 mutations rewire signaling and metabolism in del(5q) myelodysplastic neoplasms.

Stephani Schmitz, Juliette E Pearce, Sergio Martinez-Høyer, Gerjanne Vroeg In de Wei, Inge A M Snoeren, Ursula S A Stalmann, Stijn N R Fuchs, Aurelien J F Dugourd, Giulia Franciosa, Eric M Bindels, Wencke Walter, Claudia Meyer, Torsten Haferlach, Emiel P C van der Vorst, Oriol Calvete, Francesc Solé, Julio Saez-Rodriguez, Andreas Linkermann, Jesper Olsen, Hélène F E Gleitz, Rebekka K Schneider.

Deletion of chromosome 5q [del(5q)] is the most common cytogenetic abnormality in myelodysplastic neoplasms (MDS) and results in haploinsufficiency of multiple genes, including CSNK1A1. Recurrent CSNK1A1 mutations, predominantly affecting the E98 hotspot, occur almost exclusively in del(5q) MDS and are associated with adverse outcomes, yet their impact on CK1ɑ function remains unclear. Using integrated transcriptomic, (phospho)proteomic, and kinome activity profiling in hematopoietic stem and progenitor cells (HSPCs), combined with in vivo serial transplantation assays, we show that Csnk1a1 E98V represents a change-of-function rather than a loss-of-function mutation. Unlike Csnk1a1 haploinsufficiency, Csnk1a1 E98V preserves long-term hematopoietic reconstitution and does not enhance clonal expansion in vivo. Instead, the mutation induces suppression of kinase signaling networks, leading to coordinated repression of ribosomal gene expression, protein translation, and cell cycle programs. This signaling rewiring is accompanied by metabolic reprogramming characterized by reduced mitochondrial respiration, increased glycolytic flux, and an inability to adapt to metabolic challenges, creating a stress-tolerant but inflexible cellular state. Notably, Csnk1a1 E98V cells exhibit impaired megakaryopoiesis and increased vulnerability to iron overload, as well as RSL-3-mediated ferroptosis. Analysis of del(5q) MDS patients confirmed that CSNK1A1 mutations are associated with distinct clinical features, including thrombocytopenia, elevated myeloblasts, and reduced bone marrow iron levels. Together, our findings support a two-step model in which del(5q)-associated CSNK1A1 haploinsufficiency drives clonal expansion, followed by acquisition of CSNK1A1 mutations that promote stress tolerance rather than increased proliferation. This adaptive rewiring exposes metabolic and iron-dependent vulnerabilities that may be therapeutically exploited.

DOI: https://doi.org/10.1038/s41375-026-03122-x
Blood Adv. 2026 Sep 04. pii: bloodadvances.2026019895. [Epub ahead of print]

Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation.

Hyunjoo Choi, Sang-Eun Jung, Yesenia Earth, Hyojung Paik, Shuyang Lin, Jiye Yi, Maggie J Cox, Stephen M Sykes, Stephen T Oh, Yoon-A Kang.

Unfolded protein response (UPR) promotes protein homeostasis under endoplasmic reticulum stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcgR- MPP3 generates erythroid lineage and Jak2V617F mutation leads to overproduction of erythroid cells by expanding FcgR- MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcgR- MPP3 transition to granulocyte/macrophage progenitor producing FcgR+ MPP3 at the expense of erythroid lineage via the XBP1 pathway. Under a disease condition, UPR signaling cooperates with Jak2V617F mutation and exacerbates disease phenotype in a mouse model of polycythemia vera (PV) through the ATF4 pathway. Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.

DOI: https://doi.org/10.1182/bloodadvances.2026019895
Cytotherapy. 2026 Apr 20. pii: S1465-3249(26)00858-3. [Epub ahead of print]28(11): 102897

The evolving role of umbilical cord blood in transplantation, immunotherapy, and regenerative medicine: a brief contemporary review by the ISCT lab practices committee.

Rajdeep Das, Elena Maryamchik, Jelena Holovati, Mariana Morato-Marques, Medhat Askar, Nadim Mahmud, Wanxing Cui, Yvette C Tanhehco, Joseph Yossi Schwartz.

  Umbilical cord blood (UCB) is a rich source of hematopoietic stem and progenitor cells (HSPCs), mesenchymal stromal cells (MSCs), and diverse immune cell subsets with unique developmental and functional properties. These characteristics have established UCB as an important graft source for hematopoietic stem cell transplantation (HSCT) and an emerging platform for next-generation immunotherapies and regenerative applications. Importantly, cord blood transplantation remains most widely used in pediatric patients, who constitute the majority of UCB transplant recipients due to favorable tissue compatibility and hematopoietic reconstitution kinetics and the suitability of single-unit UCB grafts. Advances in donor recruitment, processing, cryopreservation, ex vivo expansion, and cell engineering continue to broaden the clinical utility of UCB while addressing historical limitations related to cell dose and engraftment kinetics. This review summarizes current biological insights, key aspects of banking infrastructure and the regulatory landscape, established and investigational therapeutic uses, and the evolving challenges and opportunities that will shape the future integration of UCB usage beyond graft source for HSCT.

Keywords:  CAR-NK cells; cellular therapy; hematopoietic stem cell transplantation; immunotherapy; natural killer cells; regenerative medicine; regulatory T cells; umbilical cord blood

DOI:  https://doi.org/10.1016/j.jcyt.2026.102897
Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2608310123

AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.

Shuyi Li, Shujiao He, Yongwei Su, Lei Wang, Yiran Wang, Yuanyuan Xu, Li Yu, Jingfeng Zhou.

  Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.

Keywords:  AML1-ETO; NAT10; ac4C; leukemia stem cells; t(8;21)

DOI:  https://doi.org/10.1073/pnas.2608310123
Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00434-9. [Epub ahead of print] 103017

Non-genetic remodeling drives leukemia propagation and reveals actionable vulnerabilities in acute myeloid leukemia.

Clement Larrue, Paolo Angelino, Sarah Mouche, Alexa S Green, Emeline Boet, Ismael Boussaid, Claudia Perez-Carretero, Rudy Birsen, Maxime Sajot, Thomas A Mckee, Ambrine Sahal, Nicolas Chapuis, François Vergez, Christian Recher, Véronique Mansat-De Mas, Olivier Kosmider, Pierre Sujobert, Frederic Catez, Jean-Jacques Diaz, Jean-Emmanuel Sarry, Petros Tsantoulis, Jerome Tamburini.

  Acute myeloid leukemia (AML) persistence and relapse are sustained by leukemia-propagating cells, yet the molecular programs supporting their expansion during disease evolution remain incompletely understood. Using serial patient-derived xenotransplantation, we establish a longitudinal model in which leukemia-initiating capacity progressively increases. Integrated single-cell transcriptomics and multi-omics profiling reveal a predominantly non-genetic trajectory that follows a conserved pattern across models and is associated with coordinated changes across epigenetic, transcriptional, and proteomic layers. Ribosome profiling and rRNA 2'-O-methylation analyses further support a stage-specific increase in translational activity with ribosome remodeling in advanced xenografts. A pharmacological screen of 3,247 compounds uncovers a limited set of vulnerabilities that consistently emerge during disease progression, including CRBN-dependent degradation of GSPT1 (CC-885) and IAP antagonism (AZD5582). In vivo validation shows that both agents markedly reduce leukemic burden, impair leukemia propagation, and enhance cytarabine activity in patient-derived xenograft (PDX) models. Together, these findings show that leukemic propagation is driven by a non-genetic remodeling program, providing a framework to prioritize and test stage-specific therapeutic strategies in AML.

Keywords:  DNA methylation; acute myeloid leukemia; drug screening; leukemic stem cells; patient-derived xenografts; ribosome profiling; serial xenotransplantation; translational regulation

DOI:  https://doi.org/10.1016/j.xcrm.2026.103017
Leukemia. 2026 Sep 02.

KLF4/MLL3 complex axis drives NRBP2 transcription to eliminate acute myeloid leukemia cells.

Meng Yang, Ting Lu, Yicheng He, Cong Chen, Yifei Wang, Guohuan Sun, Yawei Zheng, Jiaxin Qin, Jiali Ye, Xiaowei Xie, Xiangnan Zhao, Honglin Duan, Biao Zhang, Yapu Li, Fang Dong, Chang Xu, Tao Cheng, Hui Cheng, Shangda Yang.

Acute myeloid leukemia (AML) is a heterogeneous malignancy rooted in hematopoietic stem cell dysregulation. Here, we identify the transcription factor Krüppel-like factor 4 (KLF4) as a potent suppressor of AML growth, with KLF4 overexpression markedly impairing AML cell proliferation. Mechanistically, KLF4 interacts with the lysine methyltransferase 2 C (MLL3/KMT2C) histone methyltransferase complex to activate transcription of nuclear receptor-binding protein 2 (NRBP2), a pseudokinase. Furthermore, integrated transcriptomic and functional analyses identify TNIK (TRAF2- and NCK-interacting kinase) as a pro-leukemic downstream effector restrained by the KLF4-NRBP2 axis. Pharmacological inhibition of TNIK with TNIK-IN-1 inhibits AML cell growth while exerting limited effects on normal hematopoietic cells. Together, these findings establish a KLF4/MLL3 complex-NRBP2 regulatory axis that restrains AML growth through suppression of TNIK expression and provide a rationale for further preclinical evaluation of TNIK inhibition as a therapeutic strategy in AML. Schematic model illustrating the mechanism by which the KLF4/MLL3 complex/NRBP2 axis regulates the progression of AML. In AML cells with basal KLF4 expression, higher expression of TNIK promotes the proliferation of AML cells (upper). Upon KLF4 overexpression, the TRD and ZnF domains of KLF4 bind to MLL3, which facilitates the recruitment of the MLL3 complex to the NRBP2 cis-regulatory regions. This activates NRBP2 transcription and subsequently downregulates TNIK expression, leading to the suppression of AML cell proliferation. Pharmacological inhibition of TNIK by TNIK-IN-1 reduces TNIK protein levels, represses AML cell growth, and induces cell apoptosis (lower). This study reveals a molecular mechanism by which KLF4 governs AML progression, providing a novel therapeutic target and a potential small-molecule inhibitor for AML treatment (Created in BioRender. he, Y. (2026) https://BioRender.com/q0q3j3q ).

DOI: https://doi.org/10.1038/s41375-026-03117-8
Nat Commun. 2026 Sep 04. pii: 9151. [Epub ahead of print]17(1):

Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity.

Diego Gilioli, Simona Fusco, Teresa Tavella, Tatiana Volpari, Antonella Santoro, Martin Schönlein, Kety Giannetti, Edoardo Carsana, Nicolò Gualandi, Roberta Noberini, Chiara Brombin, Salvatore Russo, Sara Feola, Yvonne Giannoula, Rui M M Branca, Janne Lehtiö, Tiina M Sikanen, Markus Haapala, Laura Passerini, Angela Andrisani, Giacomo Farina, Alessia Zangari, Anastasia Conti, Lucrezia Della Volpe, Matteo Barcella, Stefano Beretta, Federico Mario Aletti, Matteo Giovanni Carrabba, Silvia Gregori, Chiara Bonini, Ivan Merelli, Fabio Ciceri, Vincenzo Cerullo, Tiziana Bonaldi, Luca Vago, Clemens A Schmitt, Raffaella Di Micco.

Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.

DOI: https://doi.org/10.1038/s41467-026-76853-1
Oncogene. 2026 Sep 04.

A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.

Marija A Zarocsinceva, Moosa Qureshi, Nicola K Wilson, George Giotopoulos, Blaise Musabe, Katherine H M Sturgess, M S Vijayabaskar, Sarah J Kinston, Ryan Asby, David J Adams, Brian J P Huntly, Fernando J Calero-Nieto, Berthold Göttgens.

Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-derived CEBPA mutation into Hoxb8-FL multipotent murine progenitors and transplanted them into syngeneic mice, capturing a clinically silent premalignant stage. All recipients developed overt disease after ~12 months with 100% penetrance and all acquired secondary RTK-RAS mutations, often with identical amino acid changes to those in patients. Single-cell transcriptomics and phenotypic profiling showed that premalignant mutant cells adopt a plasmacytoid dendritic progenitor-like state in vitro which generates both myeloid and B-lymphoid lineages during premalignancy in vivo, with individual tumours restricted to one lineage. The specificity for RTK-RAS mutations coupled with ongoing differentiation, reflects clinically relevant biological contexts thus providing a tractable model of myeloid neoplasm for mechanistic studies and drug discovery.

DOI: https://doi.org/10.1038/s41388-026-03964-w
J Clin Invest. 2026 Sep 01. pii: e204701. [Epub ahead of print]

XY0206 targets FLT3-dependent resistance states in acute myeloid leukemia.

Long Shen, Yang Yang, Chenghua Xu, Bo Jiang, Xiaoxiao Duan, Xianfeng Shao, Simeng Li, Siyi Liu, Chao Huang, Lin Song, Mingyuan Sun, Jinting Fan, Ning Wang, Dong Zhang, Youyang Fang, Lichun Kang, Yajun Jiang, Mingming Niu, Junyuan Qi, Tao Cheng, Hong Wang.

  Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive aggressive acute myeloid leukemia (AML) and confer poor prognosis. Although FLT3 inhibitors have improved outcomes, their efficacy is frequently limited by microenvironment-mediated signaling and treatment-emergent resistance. XY0206 is a structurally optimized derivative of sunitinib, an inhibitor approved for multiple solid tumors. Biochemical, multi-omics, and functional analyses showed that XY0206 directly engages FLT3 and suppresses downstream STAT5, AKT, and ERK signaling, resulting in apoptosis in FLT3-ITD AML cells. Across models of FLT3-dependent resistance, XY0206 retained antileukemic activity, including in FLT3-ITD cells harboring the F691L gatekeeper mutation, a recurrent alteration conferring resistance to approved FLT3 inhibitors. In primary AML blasts and xenograft models, XY0206 exhibited enhanced antileukemic activity with favorable tolerability relative to gilteritinib. In a phase I/II trial (NCT04471064) of XY0206 monotherapy in patients with relapsed or refractory (R/R) AML, XY0206 achieved a composite complete remission rate (CRc) of 45.7% overall, with a notable 60.0% CRc rate among patients with FLT3-ITD mutations. Three of eight patients with prior FLT3 inhibitor-exposed R/R AML also achieved CRc. Together, these findings support further clinical evaluation of XY0206 as a FLT3-directed therapeutic in AML, particularly in disease settings with reduced sensitivity to existing FLT3 inhibitors.

Keywords:  Cell biology; Clinical Research; Clinical trials; Drug therapy; Hematology; Leukemias

DOI:  https://doi.org/10.1172/JCI204701
Blood. 2026 Sep 02. pii: blood.2026033534. [Epub ahead of print]

CXXC1-dependent IRF4 activity promotes myeloma cell fitness and sustains lenalidomide resistance.

Pierangela M R Sabbattini, Nikolaos Trasanidis, Jason Taslim, Harry Whitwell, Yiming Huang, Valentina S Caputo, Han Leng Ng, Aristeidis Chaidos, Katrina Fordwor-Hepburn, Qizhen Jia, Alexia Katsarou, Maria Atta, Marco Bua, Jose Ros-Soto, Irene Roberts, Niklas Feldhahn, Nicholas Crump, Anastasios Karadimitris.

Regulation of oncogenic transcriptional programs in multiple myeloma requires the interplay of histone modifications, their writers and readers with lineage-affiliated transcription factors. The transcription factors IKZF1/3, IRF4 and MYC form an aberrant, myeloma-specific regulatory loop that drives myelomagenesis and resistance to immunomodulatory drugs (IMiDs) such as lenalidomide. Chromatin-based mechanisms that regulate these processes remain incompletely understood. Here we investigate the role of CXXC1, a core component of the H3K4 methyltransferase complex COMPASS, in the activity of the IKZF1/3-IRF4-MYC regulatory loop. We find that clinically, high CXXC1 expression is associated with high-risk proliferative, adverse prognosis disease. Consistent with this, CXXC1 is a myeloma dependency and it regulates cellular fitness programs including cell cycle, MYC targets and DNA damage response. High CXXC1 expression in primary myeloma cells is associated with higher chromatin accessibility, while acute depletion of degron-tagged CXXC1 further validates its role in regulating myeloma cell fitness programs and high-risk transcriptional signatures. CXXC1 interacts with and extensively co-binds to chromatin with IRF4 and IKZF3. Notably, in both lenalidomide-sensitive and -resistant myeloma cells, CXXC1 depletion results in loss of IRF4 and IKZF3 chromatin binding and in parallel it 'breaks' the IRF4 transcriptional self-regulatory loop. Thus, CXXC1 and COMPASS emerge as novel therapeutic targets in IMiD-sensitive and -resistant myeloma by regulating the activity of IRF4 and essential myeloma cell fitness programs.

DOI: https://doi.org/10.1182/blood.2026033534
Nat Struct Mol Biol. 2026 Aug 31.

A single-amino-acid cleavage controls global mitochondrial complex integrity.

Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.

Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.

DOI: https://doi.org/10.1038/s41594-026-01876-7
Nat Genet. 2026 Sep 01.

A single-cell atlas of multiple myeloma defines malignant archetypes and proliferative states.

Mor Zada, Anna Kurilovich, Noam Shapira, Shuang-Yin Wang, Reut Sharet-Eshed, Shlomit Kfir-Erenfeld, Miriam Schlossberg, Elina Zorde, Nathalie Asherie, Chamutal Gur, Paulina Chalan, Rotem Shalita, Maya Ben Yehuda, Pascale Zwicky, Michelle von Locquenghien, Florian Ingelfinger, Kfir Mazuz, Eyal David, Anna Gurevich-Shapiro, Natan Melamed, Iuliana Vaxman, Irit Avivi, Assaf Weiner, Polina Stepensky, Yael Cohen, Ido Amit.

Multiple myeloma (MM) is a plasma-cell malignancy with extensive genomic and transcriptional heterogeneity, limiting disease classification and precision therapy. Here we generated a clinically annotated, population-scale, single-cell atlas of MM from 341 individuals spanning the disease and treatment continuum. We identified five recurrent malignant transcriptional archetypes and an orthogonal proliferative program associated with genomic features, therapeutic resistance and clinical outcomes. Validation in the independent CoMMpass cohort demonstrated robustness, prognostic relevance and portability across platforms. We developed a single-cell, target-discovery pipeline prioritizing malignant enrichment, cell-type specificity and tissue restriction, identifying FCRL2 as a plasma-restricted or B cell-lineage-restricted surface target expressed by malignant plasma cells. FCRL2-targeted chimeric antigen receptor T cells demonstrated antigen-specific activity in vitro and survival benefit in vivo. Together, these data provide a clinically actionable blueprint for patient stratification and precision target nomination in plasma-cell malignancies.

DOI: https://doi.org/10.1038/s41588-026-02725-5
Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930

MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.

Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.

  Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.

Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage

DOI:  https://doi.org/10.1016/j.celrep.2026.117930
Blood Cancer Discov. 2026 Sep 01.

Spatial profiling identifies a distinct and topographically-defined tumor microenvironment that emerges during multiple myeloma evolution.

Marnix Koops, Luca Bertamini, Natalie Papazian, Charlotte Korst, Mátyás János Budai, Remco M Hoogenboezem, Mathijs A Sanders, Bronno van der Holt, Mark van Duin, Annemiek Broijl, Péter Balogh, Sonja Zweegman, Marc Hgp Raaijmakers, Niels W C J van de Donk, Zoltán Kellermayer, Pieter Sonneveld, Tom Cupedo.

The pathobiology of multiple myeloma is influenced by cells of the bone marrow, but whether tumor support is organized in a spatially-defined tumor microenvironment (TME) remains unclear. Using spatial transcriptomics and imaging mass cytometry, we show that myeloma cells initially exist as scattered cells throughout the marrow, yet with disease evolution condense into a spatially-defined TME. Dense tumor nodules contain a cellular ecosystem distinct from the surrounding marrow, enriched for macrophages, conventional dendritic cells, and CD8⁺ T cells, as well as endothelial cells and THY1⁺ mesenchymal stromal cells. Conversely, neutrophil lineage cells are absent from this TME but interact with scattered myeloma cells outside of dense nodules. Presence of the dense tumor architecture at diagnosis confers a worse prognosis, emphasizing the relevance of spatial organization of the bone marrow. Together, these findings define a discrete spatial and cellular myeloma TME, that provides spatially-guided insights into patient stratification and disease pathobiology.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0080
Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381

Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.

Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.

Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.

DOI: https://doi.org/10.1016/j.redox.2026.104381
Methods Mol Biol. 2026 ;3070 349-395

Computational and Statistical Framework for Quantitative Proteomics Analysis.

Ismail Kirrout, Nuria Montes.

  Mass spectrometry-based quantitative proteomics usually produces large datasets that require exhaustive analysis to extract underlying biological information. This chapter presents a step-by-step pipeline for the statistical and computational analysis of such data, oriented and generalizable to any mass spectrometry-derived proteomic dataset. These steps include: (i) data preprocessing and quality control, (ii) identification of differentially abundant proteins through statistical modeling, (iii) functional enrichment analyses, including Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA) to integrate proteomic changes in the context of biological processes and pathways, and, finally, (iv) interactome (protein-protein interaction) construction and visualization to situate proteomic alterations within signaling networks. Throughout, reproducible off-the-shelf R code and practical guidance for each step are provided, facilitating an end-to-end analysis from raw proteomic data to the biological interpretation, illustrated with visualization examples and best-practice recommendations. The complete script and necessary files are freely available at https://github.com/UMBB-IIS-Princesa/Quantitative-Proteomics-Pipeline.

Keywords:  Computational; Proteomics; Proteomics-analysis

DOI:  https://doi.org/10.1007/978-1-0716-5515-3_20
Blood Cancer Discov. 2026 Sep 02.

Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.

Qingyu Luo, Karley S Whalen, Xiaowei Wu, Amanda L Fortune, Jacqueline S Garcia, Kate Marinchev, Lin Zhang, Weiye Qian, Evangeline G Raulston, Yabing Nan, Christopher A G Booth, Kezhi Yan, David E Root, John G Doench, Andrew A Lane.

Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, whose depletion sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its ZC3H4-mediated nuclear mRNA degradation. KHSRP depletion therefore enhanced the synergistic cytotoxicity of vitamin C and uric acid, particularly in therapy-persistent leukemia cells. Re-expression of TET2 overrode the chemosensitizing effect of KHSRP depletion in TET2-mutant leukemia, suggesting that KHSRP-linked phenotypes were related to vitamin C and uric acid-mediated TET activation. These findings nominate targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0030
Blood. 2026 Sep 02. pii: blood.2025032877. [Epub ahead of print]

Vitamin C promotes differentiation of stress-specific erythroid progenitors in stress erythropoiesis.

Hsi-Hsien Hsieh, Yue Ma, Andrew W DeVilbiss, Stefano Comazzetto, Indhumathy Subramaniyan, Ji Hyung Jun, Richard A Voit, Li Li, Michail Agathocleous, Lily Jun-Shen Huang.

We discovered that vitamin C import through the vitamin C transporter SLC23A2 in stress-specific erythroid progenitors represents a key regulatory nexus in the recovery of the erythron. In response to erythroid stress, such as blood loss, Epo induces the expression of Slc23a2 in stress erythroid progenitor cells, increasing intracellular vitamin C levels and promoting their differentiation into erythroblasts. Vitamin C-induced erythroid differentiation is blocked by Slc23a2 deletion or in EpoR mutant mice unable to induce Slc23a2. Both mice show attenuated erythron recovery in stress. These defects are rescued by exogenous expression of either SLC23A2 or the related vitamin C transporter SLC23A1, but not by a transport-defective SLC23A2 mutant. Mechanistically, intracellular vitamin C promotes erythroid progenitor differentiation independently of its antioxidant activity. Instead, it regulates 2-oxoglutarate-dependent dioxygenases, TET2, KDM6A and ALKBH8, facilitating the upregulation of the master erythroid transcription factor GATA1. These findings identify vitamin C uptake as an Epo-licensed, rate-limiting determinant of stress erythropoiesis.

DOI: https://doi.org/10.1182/blood.2025032877