bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2026–03–15
seventeen papers selected by
William Grey, University of York
  1. NCOA2 promotes the return of hematopoietic stem cells to quiescence after irradiation stress by regulating FOXO3a-dependent mitophagy.
  2. Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.
  3. METTL16 enhances proteasome inhibitor resistance in multiple myeloma by inhibiting eIF2α-PERK interaction and promoting PSMB5 translation.
  4. Loss of splicing factor RBM25 promotes the collapse of murine hematopoiesis.
  5. Metabolic and epigenetic interplay in HSPC specification: A balance between extrinsic and intrinsic cues.
  6. Assessing the contributions of noncoding RNAs in acute myeloid leukemia.
  7. Sustained MYC Overexpression Drives Myeloid Differentiation Block and Acquisition of Leukemic Phenotypes.
  8. Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics.
  9. Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukaemia.
  10. Experimental and data modeling approaches of umbilical cord blood allogenic response identify cytokine profiles as potential biomarkers associated with the initial stages of alloreactivity and immunomodulation.
  11. NSUN2-FOSB reciprocity facilitates leukemogenesis in an m5C-dependent manner by increasing BCL2L1 expression.
  12. Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
  13. Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
  14. Immunophenotypic changes following menin inhibition in acute myeloid leukemia.
  15. Stem cells resume asymmetric division upon niche re-entry through reactivating the centrosome orientation checkpoint.
  16. A mechanism to initiate emergency type 2 myelopoiesis.
  17. Does coordinated targeting of metabolism and autophagy, modulated by microtubule dynamics, influence therapeutic vulnerability to eribulin in glioblastoma?
  1. Hemasphere. 2026 Mar;10(3): e70334
    NCOA2 promotes the return of hematopoietic stem cells to quiescence after irradiation stress by regulating FOXO3a-dependent mitophagy.
    Fang Chen, Naicheng Chen, Linjie Wang, Hao Zeng, Yukai Lu, Yanying Liu, Jing Chen, Yang Xu, Mo Chen, Song Wang, Mingqiang Shen, Junping Wang, Mengjia Hu.
      Hematopoietic stem cells (HSCs) are responsible for replenishing blood cells under stress conditions through increasing proliferation and differentiation. After the hematopoietic function has reconstructed, HSCs must re-enter a quiescent state to avoid their depletion, whereas the underlying mechanisms remain to be elucidated. Here, we show that the translocation of nuclear receptor coactivator 2 (NCOA2) into the nucleus is gradually increased in HSCs during the hematopoietic recovery phase after sub-lethal dose irradiation (IR). Although deletion of NCOA2 only slightly affects the steady state hematopoiesis, its deficiency leads to HSC pool exhaustion and delayed hematopoietic recovery after exposure to IR. Further investigations reveal that loss of NCOA2 decreases the quiescence, survival, and long-term reconstituting ability of HSCs following IR due to increased mitochondria-derived oxidative stress. Mechanistically, NCOA2 promotes the clearance of activated or damaged mitochondria by coactivating FOXO3a-dependent transcription of PINK1, which drives HSCs to return to quiescence after being activated by IR stress. Collectively, our findings demonstrate a critical role of NCOA2 in facilitating the restoration of HSC homeostasis after IR via the FOXO3a-PINK1-mediated mitophagy axis and thus provide an additional strategy to prevent hematopoietic failure induced by IR.
    DOI:  https://doi.org/10.1002/hem3.70334
  2. Blood Neoplasia. 2026 May;3(2): 100202
    Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia.
    Yoke Seng Lee, Jonathan D Good, Noha Awais, Benjamin K Eschle, Maia S Lineberry, Jingting Lin, Mark Wunderlich, Jenna Thibodeau, Holly Edwards, Jessica L Teo, Sarah Bibeau, Morgan Wollman, George Karadimov, Nurefsan Sariipek, Basit Salik, Jean Acosta, Jenny Noel, David G J Cucchi, Erica A K DePasquale, Prafulla C Gokhale, Jerome Ritz, Yubin Ge, Peter G Miller, Fadi J Najm, Richard M Stone, Jacqueline S Garcia, Andrew A Lane, Courtney L Jones, Peter van Galen.
      Targeted therapies, such as the BCL-2 inhibitor venetoclax, have expanded the treatment options for patients with acute myeloid leukemia (AML), but survival remains poor because of drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex messenger RNA structures in the 5' untranslated region (UTR) of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells relative to healthy hematopoietic stem and progenitor cells. Inhibition of eukaryotic initiation factor 4A (eIF4A) with the first-in-class small molecule zotatifin reduces the translation efficiency of transcripts related to the cell cycle and oncogenic signaling via the PI3K/AKT/mTOR pathway, as shown by ribosome profiling and gene set enrichment analysis. Western blot analysis corroborated these findings and demonstrated the downregulation of AKT, STAT-5, and MCL-1, factors implicated in resistance to venetoclax-based regimens. The combination of zotatifin and venetoclax synergistically kills AML cells in vitro and induces apoptosis across AML genotypes with selectivity toward progenitor-like cells in primary AML bone marrow (BM); however, its effect in primary healthy BM is limited. Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of zotatifin and venetoclax in relapsed/refractory disease.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100202
  3. Oncogene. 2026 Mar 13.
    METTL16 enhances proteasome inhibitor resistance in multiple myeloma by inhibiting eIF2α-PERK interaction and promoting PSMB5 translation.
    Guanli Wang, Xuejie Gao, Hui Zhang, Ke Hu, Qilin Feng, Yujie Liu, Chaolu Hu, Shushan Guo, Dandan Yu, Shuaikang Chang, Xiaosong Wu, Xinyan Jia, Dong An, Yu Peng, Yi Tao, Haiyan Cai, Gege Chen, Li Zhang, Jumei Shi.
      Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, we uncover METTL16 as a regulator of MM progression and PI sensitivity via an m6A methyltransferase activity-independent mechanism of translational control. Mechanistically, METTL16 overexpression is associated with altered PERK-eIF2α interaction and reduced eIF2α phosphorylation, accompanied by increased translation of key transcripts, including PSMB5 and CCND1. Consistently, these translational outputs coincide with increased proteasome activity and proliferative capacity. Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.
    DOI:  https://doi.org/10.1038/s41388-026-03706-y
  4. Exp Cell Res. 2026 Mar 10. pii: S0014-4827(26)00099-6. [Epub ahead of print]458(1): 114982
    Loss of splicing factor RBM25 promotes the collapse of murine hematopoiesis.
    Mafalda Araújo Pereira, Mikkel Bruhn Schuster, Marta Tapia, Pedro Aragon-Fernandez, Erwin M Schoof, Bo Torben Porse.
      Whilst pre-mRNA splicing has been demonstrated to play functional roles in normal hematopoiesis, the potential importance of many splicing regulators remains unexplored. RNA-binding motif protein 25, (RBM25), is a splicing factor involved in multiple cellular functions, such as proliferation and apoptosis, in various tissues as well as in leukemia. Here, we use a conditional knock-out model to show that the fundamental role of RBM25 in alternative splicing is reflected in the pivotal role of the protein for multiple hematopoietic lineages, including long-term hematopoietic stem cells, as well as embryonic stem cells derived from gene targeted mice. In contrast, mono-allelic deletion of Rbm25 did not impair HSC self-renewal or differentiation, neither under steady-state conditions nor after proliferative stress induced by bone marrow transplantation. Thus, we demonstrate that Rbm25 is haplosufficient and required for the maintenance of normal murine hematopoiesis.
    Keywords:  Hematopoiesis; RBM25; Splicing
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114982
  5. iScience. 2026 Mar 20. 29(3): 114921
    Metabolic and epigenetic interplay in HSPC specification: A balance between extrinsic and intrinsic cues.
    Maria Kalogeraki, Vincent Rondeau, Zeina Abou Nader, Marion Espéli, Karl Balabanian.
      Hematopoietic stem and progenitor cells (HSPCs), including multipotent progenitors (MPPs), sustain lifelong blood production by integrating intrinsic metabolic and epigenetic mechanisms with extrinsic cues from the bone marrow (BM) niche. Epigenetic mechanisms interact with metabolic pathways to establish a coordinated network that supports HSPC maintenance and differentiation. Spatially defined signals within BM niches shape HSPC metabolic and epigenetic states and govern lineage specification. Herein, we review recent advances on the bidirectional relationship between metabolism and epigenetics in HSPCs, emphasizing how both intrinsic and niche-derived factors regulate fate decisions under steady-state and pathological conditions. Particular attention is given to the CXCL12/CXCR4 signaling axis, a central regulator of HSPC retention, migration, and quiescence, and its emerging role in orchestrating metabolic and epigenetic mechanisms. Integrating intrinsic regulatory networks with dynamic extrinsic signals provide a conceptual framework for understanding HSPC fate and may uncover strategies for regenerative medicine and hematological disease therapy.
    Keywords:  biological sciences; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114921
  6. Blood Neoplasia. 2026 May;3(2): 100190
    Assessing the contributions of noncoding RNAs in acute myeloid leukemia.
    Paul M Zakutansky, Austin C Boucher, John D Crispino.
      Acute myeloid leukemia (AML) is caused by uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Historically, research has emphasized the role of protein-coding genes in the development of AML. However, with the human genome project revealing that 98% of the transcriptome consists of non-protein-coding RNAs, recent studies have explored how the large classes of noncoding RNAs (ncRNAs) contribute to AML. Although there are many types of ncRNAs, much attention has been placed on understanding the function of long ncRNAs (lncRNAs) and small ncRNAs known as microRNAs (miRNAs). lncRNAs are >200 nucleotides, whereas mature miRNAs are typically 18 to 25 nucleotides. lncRNAs are involved in miRNA and protein sequestration and act as transcriptional and translational regulators, whereas miRNAs facilitate mRNA degradation and translational inhibition. In addition to lncRNAs and miRNAs, two additional types of ncRNAs, namely small nucleolar RNAs (snoRNAs) and circular RNAs (circRNAs), have recently garnered attention for their roles in AML. Here, we discuss how these four distinct classes of ncRNAs may aid in disease diagnosis and prognosis as well as the mechanisms by which their dysregulation contributes to AML.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100190
  7. Exp Hematol. 2026 Mar 06. pii: S0301-472X(26)00036-6. [Epub ahead of print] 105403
    Sustained MYC Overexpression Drives Myeloid Differentiation Block and Acquisition of Leukemic Phenotypes.
    Nicole Stokes, Saul Carcamo, Deniz Demircioglu, Xuedi Wang, Malgorzata Olszewska, Dan Hasson, Hideo Watanabe, Eirini P Papapetrou, David Dominguez-Sola.
      Overexpression of MYC is a common convergent consequence of genetic driver mutations in acute myeloid leukemia (AML). However, despite extensive research, the mechanisms by which this proto-oncogene promotes leukemogenesis remain incompletely understood. Here, we developed models of deregulated MYC expression in human pluripotent stem cell (hPSC)-derived myelopoiesis. We demonstrate that MYC overexpression from the endogenous locus, which maintains physiological regulation, results in a transient and reversible differentiation block that is insufficient for leukemogenesis. Instead, constitutive MYC overexpression from ectopic alleles, which results in a persistent block of differentiation, is necessary for driving and sustaining leukemia-associated phenotypes. These phenotypes result from the widespread disruption of epigenetic landscapes and transcription factor networks induced by MYC overexpression, underpinning differentiation arrest. Our findings shed new light on the mechanisms underlying MYC-induced malignant transformation and leukemogenesis, particularly the interplay between cellular differentiation and oncogenesis. TEASER ABSTRACT: Using hPSC-derived myelopoiesis models, we show that MYC overexpression from its endogenous locus causes a transient, reversible differentiation block that is insufficient for leukemogenesis, whereas constitutive ectopic MYC produces a persistent differentiation arrest that drives leukemia-associated phenotypes. Persistent MYC rewires epigenetic landscapes and transcription factor networks, revealing that sustained deregulation, not expression alone, underlies MYC-driven leukemic transformation.
    Keywords:  Acute Myeloid Leukemia (AML); MYC oncogene; cell differentiation; hPSC-derived myelopoiesis; leukemogenesis
    DOI:  https://doi.org/10.1016/j.exphem.2026.105403
  8. NPJ Precis Oncol. 2026 Mar 11.
    Midostaurin response in AML is shaped by a progenitor-like cell state selectively targeted by SMAC mimetics.
    Nona Struyf, Henrik Gezelius, Anders Lundmark, Chiara Barizza, Hidde Ploeger, Lucia Rico Pizarro, Mattias Vesterlund, Georgios Mermelekas, Albin Österroos, Anna Bohlin, Sofia Bengtzén, Kerstin Hamberg Levedahl, Rozbeh Jafari, Lukas M Orre, Janne Lehtiö, Päivi Östling, Brinton Seashore-Ludlow, Jessica Nordlund, Sören Lehmann, Olli Kallioniemi, Tom Erkers.
      FLT3-mutated acute myeloid leukemia (AML) remains difficult to treat due to frequent resistance to FLT3 inhibitors like midostaurin. In this study, we observed a progenitor-like CD38+CD45RA+ leukemic cell population that may be associated with midostaurin resistance. Midostaurin-resistant cells display disrupted membrane architecture and a shift in signaling from STAT5 to PI3K/AKT, favoring survival over apoptosis. Functional drug testing was consistent with clinical response to midostaurin, and together with multi-omic profiling, including single-cell and proteomic analyses, indicated the presence and relevance of this resistant phenotype. Drug combination screening revealed that co-targeting with SMAC mimetics restores apoptotic competence and selectively depletes the resistant population when combined with midostaurin. In contrast, venetoclax combinations preferentially affected CD34hi cells, underscoring distinct subpopulation vulnerabilities. These findings may point to a biologically relevant mechanism underlying midostaurin resistance.
    DOI:  https://doi.org/10.1038/s41698-026-01363-8
  9. Biochem J. 2026 Mar 12. pii: BCJ20253463. [Epub ahead of print]
    Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukaemia.
    Evie Rigby, Francesca Fasanella Masci, Akshara Narayanan, Elzbieta Kania, John A Harris, Jamie Williams, Binghua Zhang, Lijun Liu, Laura Richmond, Fengtao Zhou, Ke Ding, Ruaidhrí J Carmody, Patrick A Eyers, Karen Keeshan.
      The myeloid oncogene TRIB2 is a key driver of acute myeloid leukaemia (AML) pathogenesis, promoting chemoresistance and blocking differentiation through ubiquitin-mediated degradation of the C/EBPα transcription factor. Despite its stable and sometimes elevated expression across AML subtypes, TRIB2 remains a clinically-untargeted vulnerability. Here, we present a comprehensive investigation into TRIB2 degradation mechanisms using multimodal approaches, including CRISPR knockout, mutational protein stability, small molecule TRIB2 engagement and evaluation of a novel targeted protein degrader (TRIB2-PROTAC). We identify Afatinib, a multi-ERBB covalent inhibitor, as a rapid inducer of TRIB2 degradation, triggering AML cell death potentially via signalling pathways distinct from ERBB. Importantly, TRIB2 degradation synergized with cytarabine, the frontline AML chemotherapy, amplifying therapeutic efficacy. Mapping of TRIB2 ubiquitination sites revealed Lys-63 as critical for its own proteolytic turnover, and a Lys to Arg degradation-resistant mutant (KallR) conferred enhanced chemoresistance and increased leukaemic engraftment in vivo. CRISPR-mediated TRIB2 knockout validated an essential role in AML cell survival. Consistently, the novel TRIB2-PROTAC (compound 5K) achieved robust TRIB2 degradation and AML cell killing at low micromolar concentrations. These findings establish TRIB2 as a compelling therapeutic target in AML and demonstrate that leveraging the ubiquitin-proteasome system to degrade TRIB2 offers a promising strategy to overcome chemoresistance. This work provides strong preclinical rationale for the development of TRIB2-targeting therapies in AML.
    Keywords:  Acute myeloid leukaemia; Chemotherapy resistance; Pseudokinases; Tribbles; Ubiquitin proteasome system
    DOI:  https://doi.org/10.1042/BCJ20253463
  10. Cytokine. 2026 Mar 07. pii: S1043-4666(26)00029-3. [Epub ahead of print]202 157134
    Experimental and data modeling approaches of umbilical cord blood allogenic response identify cytokine profiles as potential biomarkers associated with the initial stages of alloreactivity and immunomodulation.
    Carlos Medina, July Constanza Buitrago, Mónica Cruz Barrera, Cristian Camilo Galindo, Gustavo Salguero.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) involves the transplantation of stem cells from a healthy donor into a recipient, leading to the interaction of two distinct immune systems, in which early alloreactive responses shape downstream immune outcomes. Umbilical cord blood (UCB) is one source of hematopoietic stem cells (HSCs) with unique immunological properties, including immediate availability, efficient HSC enrichment, and a reduced baseline frequency of alloreactive T cells. Because the initial stages of alloreactivity are orchestrated by inflammatory cytokines (iCK) such as IL-6, IL-2, TNF, IFN-γ, and TGF-β, there is growing interest in characterizing their dynamics to uncover biomarkers that define the onset and magnitude of immune activation before clinical complications arise. To address this, we established robust in vitro models of inflammation, alloreactivity, and immunomodulation using human UCB, adult peripheral blood (APB), mixed leukocyte reactions (MLR), mesenchymal stromal cells (MSC), and multiplex cytokine quantification. UCB-derived cells displayed stronger immune activation than APB cells in MLR assays and exhibited a distinct iCK secretion profile associated with CD3+ T cell activation and the initiation of inflammatory responses. Notably, these iCK signatures were modulated when MLR cultures were exposed to umbilical cord-derived MSC, demonstrating the plasticity of early cytokine networks in response to immunosuppressive signals. Application of k-means clustering enabled the identification of cytokine patterns that stratified MLR cultures into high- and low-alloreactivity groups. These results support the presence of quantifiable cytokine and chemokine profiles that may serve as candidate biomarkers for early immune activation and suppression during the initial stages of donor-recipient alloreactivity, provided they are rigorously validated in preclinical models. Collectively, these findings underscore the potential of multiplex iCK signatures as predictive tools for alloreactivity in UCB-based transplantation and pave the way for future preclinical and clinical studies focused on biomarker-driven monitoring of immune activation.
    Keywords:  Alloreactivity; Hematopoietic stem cell transplantation; Inflammation; Mesenchymal stromal cells; Mixed lymphocyte reaction; Umbilical cord blood
    DOI:  https://doi.org/10.1016/j.cyto.2026.157134
  11. Haematologica. 2026 Mar 12.
    NSUN2-FOSB reciprocity facilitates leukemogenesis in an m5C-dependent manner by increasing BCL2L1 expression.
    Bin Zhou, Yigang Yuan, Yue Cai, Jingying Zhou, Liuzhi Shi, Yaqian Qin, Chen Meng, Shixin Zhang, Shirui Yu, Xinyao Chen, Xiaofei He, Shanshan Wu, Min Li, Xuanyu Yu, Yifen Shi, Chongyun Xing, Chiqi Chen, Meng Zhao, Shenmeng Gao.
      NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modifications on RNA to regulate mRNA stability. However, its roles in normal hematopoiesis and leukemogenesis remain poorly understood. Here, we show that NSUN2 is markedly upregulated in primary AML patient samples compared with normal hematopoietic cells. NSUN2 knockdown (KD) impaired AML cell proliferation, induced apoptosis, and reduced colony formation. Genetic ablation of Nsun2 in an MLL-AF9 (MA9)-transformed murine AML model substantially impaired leukemia stem cell (LSC) self-renewal and prolonged overall survival (OS), while sparing normal hematopoiesis, highlighting NSUN2 as a potential therapeutic target. Notably, wild-type NSUN2, but not catalytically inactive mutants, restored LSC function and leukemogenesis in NSUN2-deficient AML cells, indicating that these effects are mô€€€C-dependent. Mechanistically, NSUN2 stabilized FosB proto-oncogene (FOSB) mRNA via mô€€€C modification at nucleotide 3656 in the 3′-UTR, thereby upregulating FOSB expression. In turn, FOSB transcriptionally activated NSUN2, forming a feedforward regulatory loop. Furthermore, FOSB promoted expression of the anti-apoptotic regulator B-cell lymphoma-2-like protein 1 (BCL2L1) by directly binding to its promoter. In conclusion, these findings uncover a novel NSUN2-FOSB-BCL2L1 axis that drives AML leukemogenesis in an m5C-dependent manner, suggesting the therapeutic potential for targeting this pathway.
    DOI:  https://doi.org/10.3324/haematol.2025.289250
  12. Cell Death Dis. 2026 Mar 09.
    Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
    Erin M Kropp, Sho Matono, Olivia Y Wang, Aaron M Robida, Malathi Kandarpa, Jineigh L Grant, Bryndon J Oleson, Andrew Alt, Moshe Talpaz, Matthew J Pianko, Qing Li.
      Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum-associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD has been proposed as a therapeutic strategy to overcome proteasome inhibitor resistance; however, the identification of novel inhibitors has been limited. To address this, we conducted a cell-based high-throughput screen using the FDA repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates, without affecting the degradation of key cytosolic proteins that are implicated in disease relapse. Surprisingly, although ER stress response pathways are activated after ERAD inhibition in MM, we find that apoptosis is mediated by altered lipid raft organization, leading to aberrant activation of the death-inducing signaling complex (DISC) and caspase 8 in the extrinsic apoptotic pathway. Notably, ERAD inhibition by RTA408 is cytotoxic to primary malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish a novel ERAD inhibitor, which is a valuable tool to dissect ERAD biology, and provide pre-clinical evidence for RTA408 as a therapeutic agent in MM.
    DOI:  https://doi.org/10.1038/s41419-026-08526-2
  13. iScience. 2026 Mar 20. 29(3): 115056
    Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
    Nayyerehalsadat Hosseini, Ahmed M Elshazly, Holly A Byers, Madison A Ward, Amy N Brooks, Janakiram R Vangala, Senthil K Radhakrishnan.
      The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are the primary mechanisms for protein degradation, yet the molecular mechanisms linking them remain unclear. We show that loss of the UPS shuttle-protease DDI2 in diverse human and murine cells leads to a proteotoxic stress response driven by the intracellular accumulation of the secretory protein CCN1. Misfolded CCN1 is normally extracted from the endoplasmic reticulum by a DDI2-p97 complex and directed to lysosomes for degradation. In the absence of DDI2, CCN1 builds up, produces reactive oxygen species, and triggers compensatory autophagy; CCN1 knockout or ROS scavenging attenuates this response. Loss of DDI2 also impairs CCN1-LAMP1 colocalization, suggesting that DDI2 functions as a selective cargo receptor linking the UPS and ALP. These findings reveal a stress-responsive DDI2-CCN1 axis that reshapes proteostasis and highlight DDI2 as a potential therapeutic vulnerability in proteasome-dependent cancers.
    Keywords:  Biochemistry; Biological sciences; Cancer; Cancer systems biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115056
  14. Leukemia. 2026 Mar 11.
    Immunophenotypic changes following menin inhibition in acute myeloid leukemia.
    Sanam Loghavi, Aziz Farhat, Trevor J Jamison, Georgina El Hajjar, Alex Bataller, Sa A Wang, Wei Wang, Guilin Tang, Andres E Quesada, Alexandre Bazinet, Branko Cuglievan, Courtney D DiNardo, Guillermo Montalban-Bravo, Koichi Takahashi, Nicholas J Short, Hussein A Abbas, Tapan Kadia, Farhad Ravandi, Naval Daver, Elias Jabbour, Gautam Borthakur, Michael Andreeff, L Jeffrey Medeiros, Hagop M Kantarjian, Ghayas C Issa.
      Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However, determinants of response to revumenib have not been fully elucidated. We examined the immunophenotype of leukemia cells by flow cytometry, in sequential bone marrow specimens from 48 patients with R/R AML treated with revumenib. We observed dynamic changes in the immunophenotype after treatment in 16 of 31 (52%) patients, characterized by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukemia-associated immunophenotypes. Morphologic remission with undetectable measurable residual disease (MRD) by flow cytometry following revumenib was associated with improved overall survival, with a median of 23.6 months compared with 20.8 months in patients with morphologic response and detectable MRD, and 3.2 months in non-responders. In summary, treatment monitoring of AML by flow cytometry, following menin inhibition, requires recognition of phenotypic changes associated with differentiation.
    DOI:  https://doi.org/10.1038/s41375-026-02905-6
  15. Commun Biol. 2026 Mar 09.
    Stem cells resume asymmetric division upon niche re-entry through reactivating the centrosome orientation checkpoint.
    Muhammed Burak Bener, Autumn Twillie, Naiya Patel, Mayu Inaba.
      In Drosophila testis, germline stem cells (GSCs) typically divide asymmetrically, keeping one daughter cell within the niche for self-renewal and placing the other daughter cell outside the niche to undergo differentiation. This is the primary mechanism for maintaining a stable number of stem cells in the niche. However, it has been shown that small fraction of GSCs continuously leave the niche, necessitating an additional mechanism to compensate for this loss and maintain a constant number of GSCs. Dedifferentiation and symmetric renewal have been shown to replenish lost GSCs during regenerative and physiological conditions. However, it remains unknown whether dedifferentiated GSCs reacquire native GSC behaviors. Using long-term live imaging, we trace the cells following dedifferentiation and show that dedifferentiated GSCs appear to reacquire at least one aspect of native GSC behavior, the centrosome orientation checkpoint, a GSC-specific checkpoint mechanism that ensures oriented spindle to achieve asymmetric stem cell divisions. Our findings provide important insights into the robust mechanisms ensuring asymmetric division in the niche.
    DOI:  https://doi.org/10.1038/s42003-026-09812-7
  16. Nature. 2026 Mar 11.
    A mechanism to initiate emergency type 2 myelopoiesis.
    Alexandre Fagnan, Cristina Di Genua, Yiran Meng, Roy Drissen, Zishan Zhang, Bowen Zhang, Padraic G Fallon, Vassilis Pachnis, Erika J Mancini, Fränze Progatzky, Claus Nerlov.
      Immune responses to parasite infection involve the increased production of basophils and eosinophils. These two myeloid cell types have key roles in type 2 anti-parasite immunity1 and rely on GATA family transcription factors for their specification2,3. The first committed step in basophil and eosinophil production is generation of basophil-eosinophil-mast cell progenitors (BEMPs) from oligopotent erythroid-primed multipotent progenitors (EMPPs). However, it is not well established how immune responses act on progenitors to initiate type 2 myelopoiesis. Here we show that infection with the helminth Heligmosomoides polygyrus increases EMPP commitment to myeloid fate at the expense of erythropoiesis. Upon infection with H. polygyrus, the IL-33 alarmin accumulated in the bone marrow, causing EMPPs to upregulate the GATA co-factor LMO4 and preferentially differentiate into myeloid cells. LMO4 was sufficient to instruct myeloid fate in EMPPs by interacting with GATA2, displacing the FOG1 co-factor and redistributing GATA binding from megakaryocyte-erythroid-specific to basophil, eosinophil and mast cell (BEM)-specific chromatin. Accordingly, mice carrying a GATA2 mutation that selectively impairs the LMO4-GATA2 interaction were deficient in GATA factor allocation to BEM chromatin, myeloid lineage commitment, basophil and eosinophil production, and parasite control. This identifies LMO4 as an IL-33-regulated master regulator of type 2 myelopoiesis, and transcription factor reallocation as a mechanism of lineage commitment.
    DOI:  https://doi.org/10.1038/s41586-026-10256-6
  17. Transl Cancer Res. 2026 Feb 28. 15(2): 136
    Does coordinated targeting of metabolism and autophagy, modulated by microtubule dynamics, influence therapeutic vulnerability to eribulin in glioblastoma?
    Guilherme Augusto Sousa Alcântara, João Agostinho Machado-Neto.
      
    Keywords:  Eribulin; autophagy; glioblastoma (GBM); isocitrate dehydrogenase mutations (IDH mutations); phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin signaling (PI3K/AKT/mTOR signaling)
    DOI:  https://doi.org/10.21037/tcr-2026-1-0051
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