bims-scepro 2025-05-18 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–05–18
seventeen papers selected by
William Grey, University of York

Differential regulation of fetal bone marrow and liver hematopoiesis by yolk-sac-derived myeloid cells.
Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.
GMP-like and MLP-like Subpopulations of Hematopoietic Stem and Progenitor Cells Harboring Mutated EZH2 and TP53 at Diagnosis Promote Acute Myeloid Leukemia Relapse: Data of Combined Molecular, Functional, and Genomic Single-Stem-Cell Analyses.
Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool.
Taurine from tumour niche drives glycolysis to promote leukaemogenesis.
Acute myeloid leukemia stem cells remodel the bone marrow niche via TGF-β-activated Alcam+ bone lining cells, creating a self-sustaining environment.
HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma.
Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation.
Therapeutic Effect of V8 Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by ROS and CHOP Signaling.
Galectin-1: An important regulator in myeloid differentiation and acute myeloid leukemia as well as a promising prognostic indicator and therapeutic target.
Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
Discovery of an LSD1 PROTAC degrader.
KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.
Prediction of protein subcellular localization in single cells.
Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24.
Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.

Nat Commun. 2025 May 14. 16(1): 4427

Differential regulation of fetal bone marrow and liver hematopoiesis by yolk-sac-derived myeloid cells.

Benjamin Weinhaus, Shelli Homan, Morgan Kincaid, Aryan Tadwalkar, Xiaowei Gu, Sumit Kumar, Anastasiya Slaughter, Jizhou Zhang, Qingqing Wu, J Matthew Kofron, Ty D Troutman, Tony DeFalco, Daniel Lucas.

Fetal hematopoiesis takes place in the liver before colonizing the bone marrow where it will persist for life. This colonization is thought to be mediated by specification of a microenvironment that selectively recruits hematopoietic cells to the nascent bone marrow. The identity and mechanisms regulating the specification of this colonization niche are unclear. Here we identify a VCAM1+ sinusoidal colonization niche in the diaphysis that regulates neutrophil and hematopoietic stem cell colonization of the bone marrow. Using confocal microscopy, we find that colonizing hematopoietic stem and progenitor cells (HSPC) and myeloid cells selectively localize to a subset of VCAM1+ sinusoids in the center of the diaphysis. Vcam1 deletion in endothelial cells impairs hematopoietic colonization while depletion of yolk-sac-derived osteoclasts disrupts VCAM1+ expression, and impairs neutrophil and HSPC colonization to the bone marrow. Depletion of yolk-sac-derived myeloid cells increases fetal liver hematopoietic stem cell numbers, function and erythropoiesis independent of osteoclast activity. Thus, the yolk sac produces myeloid cells that have opposite roles in fetal hematopoiesis: while yolk-sac derived myeloid cells in the bone marrow promote hematopoietic colonization by specifying a VCAM1+ colonization niche, a different subset of yolk-sac-derived myeloid cells inhibits HSC in the fetal liver.

DOI: https://doi.org/10.1038/s41467-025-59058-w
J Clin Invest. 2025 May 15. pii: e184665. [Epub ahead of print]135(10):

Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.

Chiharu Ishikawa, Laura Barreyro, Avery M Sampson, Kathleen M Hueneman, Kwangmin Choi, Sophia Y Philbrook, Issac Choi, Lyndsey C Bolanos, Mark Wunderlich, Andrew G Volk, Stephanie S Watowich, Kenneth D Greis, Daniel T Starczynowski.

  Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Keywords:  Hematology; Leukemias; Oncology; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/JCI184665
Int J Mol Sci. 2025 Apr 29. pii: 4224. [Epub ahead of print]26(9):

GMP-like and MLP-like Subpopulations of Hematopoietic Stem and Progenitor Cells Harboring Mutated EZH2 and TP53 at Diagnosis Promote Acute Myeloid Leukemia Relapse: Data of Combined Molecular, Functional, and Genomic Single-Stem-Cell Analyses.

Tal Shahar Gabay, Nofar Stolero, Niv Rabhun, Rawan Sabah, Ofir Raz, Yaara Neumeier, Zipora Marx, Liming Tao, Tamir Biezuner, Shiran Amir, Rivka Adar, Ron Levy, Noa Chapal-Ilani, Natalia Evtiugina, Liran I Shlush, Ehud Shapiro, Shlomit Yehudai-Resheff, Tsila Zuckerman.

  Acute myeloid leukemia (AML) is associated with unfavorable patient outcomes primarily related to disease relapse. Since specific types of leukemic hematopoietic stem and progenitor cells (HSPCs) are suggested to contribute to AML propagation, this study aimed to identify and explore relapse-initiating HSPC subpopulations present at diagnosis, using single-cell analysis (SCA). We developed unique high-resolution techniques capable of tracking single-HSPC-derived subclones during AML evolution. Each subclone was evaluated for chemo-resistance, in vivo leukemogenic potential, mutational profile, and the cell of origin. In BM samples of 15 AML patients, GMP-like and MLP-like HSPC subpopulations were identified as prevalent at relapse, exhibiting chemo-resistance to commonly used chemotherapy agents cytosine arabinoside (Ara-C) and daunorubicin. Reconstruction of phylogenetic lineage trees combined with genetic analysis of single HSPCs and single-HSPC-derived subclones demonstrated two distinct clusters, originating from MLP-like or GMP-like subpopulations, observed both at diagnosis and relapse. These subpopulations induced leukemia development ex vivo and in vivo. Genetic SCA showed that these relapse-related subpopulations harbored mutated EZH2 and TP53, detected already at diagnosis. This study, using combined molecular, functional, and genomic analyses at the level of single cells, identified patient-specific chemo-resistant HSPC subpopulations at the time of diagnosis, promoting AML relapse.

Keywords:  acute myeloid leukemia (AML); hematopoietic stem and progenitor cells (HSPCs); leukemogenic potential; relapse; single cell analysis (SCA)

DOI:  https://doi.org/10.3390/ijms26094224
Nat Commun. 2025 May 14. 16(1): 4428

Embryonic macrophages orchestrate niche cell homeostasis for the establishment of the definitive hematopoietic stem cell pool.

Gülce Perçin, Konstantin Riege, Julia Fröbel, Jonas Metz, Stephan Culemann, Mathias Lesche, Susanne Reinhardt, Thomas Höfer, Steve Hoffmann, Claudia Waskow.

Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. Presence of embryonic macrophages in the bone marrow and functional impact on hematopoietic stem cells (HSC) or the niche remains unclear. Here we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult origin. Newborn mice lacking embryonic macrophages have decreased HSC numbers in the bone marrow suggesting an important function for embryo-derived macrophages in orchestrating HSC trafficking around birth. The establishment of a normal cellular niche space in the bone marrow critically depends on embryonic macrophages that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived macrophages in the establishment of the niche environment pivotal for the establishment of a normally sized HSC pool.

DOI: https://doi.org/10.1038/s41467-025-59059-9
Nature. 2025 May 14.

Taurine from tumour niche drives glycolysis to promote leukaemogenesis.

Sonali Sharma, Benjamin J Rodems, Cameron D Baker, Christina M Kaszuba, Edgardo I Franco, Bradley R Smith, Takashi Ito, Kyle Swovick, Kevin Welle, Yi Zhang, Philip Rock, Francisco A Chaves, Sina Ghaemmaghami, Laura M Calvi, Archan Ganguly, W Richard Burack, Michael W Becker, Jane L Liesveld, Paul S Brookes, Joshua C Munger, Craig T Jordan, John M Ashton, Jeevisha Bajaj.

Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1-5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC-niche interactions that are essential for leukaemogenesis. These analyses identify the taurine-taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.

DOI: https://doi.org/10.1038/s41586-025-09018-7
Leukemia. 2025 May 13.

Acute myeloid leukemia stem cells remodel the bone marrow niche via TGF-β-activated Alcam+ bone lining cells, creating a self-sustaining environment.

Ngan Thi Kim Nguyen, Hisayuki Yao, Kentaro Hosokawa, Yuki Esaki, Ryosuke Yuta, Shunichi Adachi, Fumio Arai.

DOI: https://doi.org/10.1038/s41375-025-02640-4
Cell Rep. 2025 May 14. pii: S2211-1247(25)00491-7. [Epub ahead of print]44(5): 115720

HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma.

Na Shen, Yuan Xia, Xuxing Shen, Wei Hua, Min Shi, Lijuan Chen.

  Ferroptosis, a regulated cell death triggered by overload-dependent lipid peroxidation, is implicated in multiple human cancers. The mechanisms underlying ferroptosis in multiple myeloma (MM) remain enigmatic. Here, we confirmed that HSPA9 is overexpressed in MM samples and correlates with unfavorable outcomes. Functionally, HSPA9 enhances MM cell viability, ferroptosis resistance, and tumorigenicity, suggesting its oncogenic role. Proteomics screening identified SLC7A11, a key ferroptosis suppressor, as a HSPA9 interactor. Mechanistically, HSPA9 serves as a bridge to strengthen the interaction between USP14 and SLC7A11, modulating USP14-mediated SLC7A11 deubiquitination. Furthermore, the inhibition of USP14 with IU1 enhances the SLC7A11 ubiquitination and degradation, promoting ferroptosis and showing therapeutic efficacy in MM xenograft models. Clinically, HSPA9, USP14, and SLC7A11 expression are positively correlated in MM samples, which have a prognostic value. Our study reveals HSPA9-USP14-SLC7A11 axis as a key regulator of ferroptosis in MM and a potential therapeutic target.

Keywords:  CP: Cancer; HSPA9; SLC7A11; USP14; deubiquitination; multiple myeloma

DOI:  https://doi.org/10.1016/j.celrep.2025.115720
PLoS Pathog. 2025 May 13. 21(5): e1013170

Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.

María Sobén, Paula Guerrero, Andrea Guiu, Alberto Yáñez, M Luisa Gil.

Central trained immunity, induced via reprogramming of hematopoietic stem and progenitor cells (HSPCs), mediates sustained heightened responsiveness of mature myeloid cells to secondary challenges. We have previously demonstrated that HSPCs use TLR2 and Dectin-1 to sense Candida albicans to induce the production of trained monocytes/macrophages to fight against secondary infection. Neutrophils play an important role in innate immunity and are critical for clearance of C. albicans. In this work, we used an in vitro model of mouse HSPC differentiation to investigate the functional phenotype of neutrophils derived from HSPCs exposed to various PAMPs and C. albicans cells. We found that neutrophils derived from HSPCs stimulated by a TLR2 agonist exhibit reduced inflammatory cytokine production (tolerized neutrophils) whereas neutrophils generated from a Dectin-1 agonist or C. albicans stimulated HSPCs produce higher amounts of cytokines (trained neutrophils). We further demonstrated that a transient exposure of HSPCs to live C. albicans cells is sufficient to induce a trained phenotype of the neutrophils they produce in a Dectin-1- and TLR2-dependent manner. These trained neutrophils exhibited higher phagocytosis and microbicidal capacity than control neutrophils. Additionally, their adoptive transfer was sufficient to reduce fungal burden during invasive candidiasis. Mechanistically, we demonstrated that trained neutrophils use mitochondrial ROS (mtROS) to enhance their ability to kill C. albicans cells, as they produce higher amounts of mtROS and scavenging mtROS with MitoTEMPO attenuated their yeast-killing ability to match that of control neutrophils. Altogether, these data suggest that infection-experienced HSPCs contribute to trained immunity by providing a source of trained neutrophils with enhanced antimicrobial activity which may confer prolonged protection from infection. The tailored manipulation of this mechanism might offer new therapeutic strategies for controlling fungal infections by harnessing neutrophils.

DOI: https://doi.org/10.1371/journal.ppat.1013170
Cell Rep. 2025 May 14. pii: S2211-1247(25)00476-0. [Epub ahead of print]44(5): 115705

Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation.

Joana R Costa, Yang Li, Nurkaiyisah Zaal Anuar, David O'Connor, Sunniyat Rahman, Tanya Rapoz-D'Silva, Kent T M Fung, Rachael Pocock, Zhaodong Li, Stephen Henderson, Lingyi Wang, Mateja E Krulik, Sara Hyseni, Nivedita Singh, George Morrow, Yanping Guo, Daisy O F Gresham, Javier Herrero, Richard G Jenner, A Thomas Look, Dennis Kappei, Marc R Mansour.

  The TAL1 oncogene driving T cell lymphoblastic leukemia is frequently activated through mutated cis-regulatory elements, whereby small insertions or deletions (indels) create a binding site for the transcription factor MYB. Unraveling how non-coding mutations create oncogenic enhancers is key to understanding cancer biology and can provide important insights into fundamental mechanisms of gene regulation. Utilizing a CRISPR-Cas9 screening approach, we identify GATA3 as the key transcriptional regulator of enhancer-mediated TAL1 overexpression. CRISPR-Cas9 engineering of the mutant enhancer reveals a tandem GATA3 site that is required for binding of GATA3, chromatin accessibility, and MYB recruitment. Reciprocally, MYB binding to its motif is required for GATA3 recruitment, consistent with a transcription factor cooperativity model. Importantly, we show that GATA3 stabilizes a TAL1-MYB interaction and that complex formation requires GATA3 binding to DNA. Our work sheds light on the mechanisms of enhancer-mediated oncogene activation, where key transcription factors cooperate to achieve maximal transcriptional output, thereby supporting leukemogenesis.

Keywords:  CP: Cancer; CP: Molecular biology; DNA binding domain; GATA3; MYB; T cell acute lymphoblastic leukemia; T-ALL; TAL1; cooperativity; enhancer; motif; oncogene; transcription factor

DOI:  https://doi.org/10.1016/j.celrep.2025.115705
FASEB J. 2025 May 15. 39(9): e70622

Therapeutic Effect of V8 Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by ROS and CHOP Signaling.

Yong-Jian Guo, Meng-Yuan Zhu, Zhan-Yu Wang, Hong-Yu Chen, Ying-Jie Qing, Hong-Zheng Wang, Jing-Yan Xu, Hui Hui, Hui Li.

  Acute myeloid leukemia (AML) is characterized by the malignant proliferation of abnormally or poorly differentiated myeloid cells in the hematopoietic system. However, there is a lack of effective drugs for treating non-M3 AML. V8, a newly synthesized derivative of the natural flavonoid wogonin, which is a potential anticancer drug, has demonstrated significant antitumor activity both in vitro and in vivo. Here, we investigated the effects of V8 on AML cell lines and primary AML cells as well as its underlying mechanisms. Our results showed that V8 exerted significant concentration-dependent growth inhibition and apoptosis induction in AML cells, accompanied by characteristic pathological features including lysosomal functions suppression, mitochondrial dysfunction, and endoplasmic reticulum stress (ERS) activation. Mechanistic investigations revealed that V8 induced mitochondrial membrane potential collapse through elevation of intracellular reactive oxygen species (ROS) levels, while concurrently blocking mitophagy via lysosomal functional inhibition. Furthermore, V8 selectively activated the PERK/p-eIF2α/ATF4 and IRE1α/XBP1 signaling axes of ERS, ultimately triggering CHOP-mediated apoptosis through the ERS-specific pathway. In vivo studies confirmed that V8 treatment significantly prolonged survival duration in NOD/SCID mice bearing primary AML xenografts and suppressed tumor progression in BALB/c nude mice with U937 cell xenografts, with antitumor efficacy closely associated with CHOP-dependent ERS pathway modulation. These findings not only elucidate the multi-targeted mechanism of V8 against AML through coordinated regulation of the ROS-mitochondria-lysosome-ERS signaling network, but also provide critical theoretical foundations for developing natural product-based therapeutics for AML. The multi-pathway synergistic characteristics exhibited by V8 underscore its considerable potential as a clinically translatable candidate drug.

Keywords:  AML; CHOP; ERS; V8; apoptosis; mitochondrial injury; mitophagy

DOI:  https://doi.org/10.1096/fj.202500599R
Int Immunopharmacol. 2025 May 15. pii: S1567-5769(25)00825-2. [Epub ahead of print]158 114835

Galectin-1: An important regulator in myeloid differentiation and acute myeloid leukemia as well as a promising prognostic indicator and therapeutic target.

Lulu Liu, Panpan Cheng, Junjie Cui, Saisai Ren, Mingkang Yao, Ling Li, Hui Zhou, Xianning Zhang, Xianyun Qin, Yaqi Liu, Hao Zhang, Lina Wang, Mingtai Chen.

  Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematological malignancy with a low survival probability and limited therapeutic options. Although galectin-1 (LGALS1) has been implicated in tumor cell survival and immune evasion in solid tumor, its role in AML is still unclear. In this study, we found that LGALS1 presents prominent upregulation in AML patients at both mRNA and protein levels compared with the control samples. Bioinformatics analysis indicated that high expression of LGALS1 is a significant unfavorable prognostic factor for overall survival in AML, correlating with adverse clinical and genetic features as well as immune cell infiltration. Depletion of LGALS1 in AML cells impeded cell proliferation, induced apoptosis and promoted myeloid differentiation. Treatment with OTX008, an LGALS1 inhibitor, markedly diminished the viability of primary malignant bone marrow cells from AML patients. Notably, LGALS1 expression was significantly reduced exclusively in AML-M5 patients after treatment, which may be due to its higher expression in AML-M5 subtype compared to other FAB subtypes. In summary, our findings indicate that LGALS1 could serve as an independent prognostic risk factor and a promising therapeutic target in AML, providing novel insights into AML pathogenesis and laying the foundation for the development of new therapeutic strategies.

Keywords:  Acute myeloid leukemia; LGALS1; Myeloid differentiation; OTX008; Prognosis

DOI:  https://doi.org/10.1016/j.intimp.2025.114835
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2415779122

Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.

Takashi Sakamoto, Julie Leca, Xin Zhang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Liam D Hendrikse, Wenjing Zhou, Thorsten Berger, Jerome Fortin, Steven M Chan, Ming-Feng Chiang, Satoshi Inoue, Wanda Y Li, Mandy F Chu, Gordon S Duncan, Andrew Wakeham, François Lemonnier, Chantal Tobin, Ryan Mcwilliam, Isabelle Colonna, Christophe Bontoux, Soode Moghadas Jafari, Robert L Bowman, Brandon Nicolay, Sebastien Ronseaux, Rohini Narayanaswamy, Ross L Levine, Ari M Melnick, Christopher E Mason, Mark D Minden, Tak W Mak.

  In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (IDH1) often co-occur with NPM1 mutations, and less frequently with FLT3 mutations. To investigate whether the effects of IDH1 mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. Idh1R132H combined with Npm1c induced overt AML, whereas Idh1R132H plus Flt3ITD resulted in Flt3ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1R132H;Npm1c cells and Idh1R132H;Flt3ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1R132H;Npm1c cells corresponded to that of human IDH-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of Idh1R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1R132H with Npm1c vs. Flt3ITD may have implications for the devising of subtype-specific treatments for human AML.

Keywords:  FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model

DOI:  https://doi.org/10.1073/pnas.2415779122
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2425812122

Discovery of an LSD1 PROTAC degrader.

Amir Hosseini, Xing Qiu, Yan Xiong, Ki Him Nicholas Chiang, Jerrel Catlett, Ines Kaltheuner, Zhijie Deng, Sudipta Ghosh, Yang Shi, Jian Jin.

  Aberrant expression of lysine-specific demethylase 1 (LSD1) has been implicated in various cancers, including acute myeloid leukemia (AML). Recent studies have revealed both catalytic and noncatalytic oncogenic functions of LSD1, which cannot be effectively addressed by traditional small-molecule inhibitors. Therefore, to remove LSD1 and mitigate its oncogenic activity, we utilized the proteolysis-targeting chimera (PROTAC) approach and developed an LSD1 PROTAC degrader MS9117, which recruits the E3 ligase cereblon (CRBN). MS9117 induces LSD1 degradation in a concentration-, time-, CRBN-, and proteasome-dependent manner. Importantly, MS9117 effectively degrades LSD1 and demonstrates superior antiproliferative effects in AML cells, compared to the existing pharmacological LSD1 inhibitors. Furthermore, MS9117 also sensitized nonacute promyelocytic leukemia AML cells to all-trans retinoic acid treatment. Moreover, we developed two negative controls of MS9117, MS9117N1 and MS9117N2, which do not degrade LSD1 or inhibit leukemia cell growth, further confirming the mechanism of action of MS9117. Overall, MS9117 serves as a valuable chemical tool and a potential therapeutic to target both the catalytic and scaffolding functions of LSD1. With several LSD1 inhibitors already in clinical development, the LSD1 degraders such as MS9117 offer an additional option for future clinical studies.

Keywords:  AML; ATRA; LSD1; PROTAC; degrader

DOI:  https://doi.org/10.1073/pnas.2425812122
J Cell Biol. 2025 Jul 07. pii: e202409157. [Epub ahead of print]224(7):

KIF2A stabilizes intercellular bridge microtubules to maintain mouse embryonic stem cell cytokinesis.

Lieke Stockmann, Hélène Kabbech, Gert-Jan Kremers, Brent van Herk, Bas Dille, Mirjam van den Hout, Wilfred F J van IJcken, Dick H W Dekkers, Jeroen A A Demmers, Ihor Smal, Danny Huylebroeck, Sreya Basu, Niels Galjart.

Cytokinesis, the final stage of cell division, serves to physically separate daughter cells. In cultured naïve mouse embryonic stem cells, cytokinesis lasts unusually long. Here, we describe a novel function for the kinesin-13 member KIF2A in this process. In genome-engineered mouse embryonic stem cells, we find that KIF2A localizes to spindle poles during metaphase and regulates spindle length in a manner consistent with its known role as a microtubule minus-end depolymerase. In contrast, during cytokinesis we observe tight binding of KIF2A to intercellular bridge microtubules. At this stage, KIF2A maintains microtubule length and number and controls microtubule acetylation. We propose that the conversion of KIF2A from a depolymerase to a stabilizer is driven by both the inhibition of its ATPase activity, which increases lattice affinity, and a preference for compacted lattices. In turn, KIF2A might maintain the compacted microtubule state at the intercellular bridge, thereby dampening acetylation. As KIF2A depletion causes pluripotency problems and affects mRNA homeostasis, our results furthermore indicate that KIF2A-mediated microtubule stabilization prolongs cytokinesis to maintain pluripotency.

DOI: https://doi.org/10.1083/jcb.202409157
Nat Methods. 2025 May 13.

Prediction of protein subcellular localization in single cells.

Xinyi Zhang, Yitong Tseo, Yunhao Bai, Fei Chen, Caroline Uhler.

The subcellular localization of a protein is important for its function, and its mislocalization is linked to numerous diseases. Existing datasets capture limited pairs of proteins and cell lines, and existing protein localization prediction models either miss cell-type specificity or cannot generalize to unseen proteins. Here we present a method for Prediction of Unseen Proteins' Subcellular localization (PUPS). PUPS combines a protein language model and an image inpainting model to utilize both protein sequence and cellular images. We demonstrate that the protein sequence input enables generalization to unseen proteins, and the cellular image input captures single-cell variability, enabling cell-type-specific predictions. Experimental validation shows that PUPS can predict protein localization in newly performed experiments outside the Human Protein Atlas used for training. Collectively, PUPS provides a framework for predicting differential protein localization across cell lines and single cells within a cell line, including changes in protein localization driven by mutations.

DOI: https://doi.org/10.1038/s41592-025-02696-1
Blood. 2025 May 15. pii: blood.2024027455. [Epub ahead of print]

Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24.

Eman Khatib-Massalha, Christian Andrea Di Buduo, Agathe L Chédeville, Ya-Hsuan Ho, Yexuan Zhu, Elodie Grockowiak, Yuki Date, Lam Tan Khuat, Zijian Fang, Jose Quesada-Salas, Eva Carrillo Félez, Matteo Migliavacca, Isabel Montero, José Antonio Pérez-Simón, Alessandra Balduini, Simón Méndez-Ferrer.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes ("emperipolesis") have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the "don't-eat-me" signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

DOI: https://doi.org/10.1182/blood.2024027455
Sci Adv. 2025 May 16. 11(20): eadq3858

Phosphorylation by Aurora kinase A facilitates cortical-cytoplasmic dynamics of Par-3 in asymmetric division of radial glia progenitors.

Jason Q Garcia, Vincent Mouilleau, Henry Ng, Xiang Zhao, David O Morgan, Su Guo.

During asymmetric cell division (ACD) of radial glia progenitors (RGPs), the cortical polarity regulator Par-3 is detected in the cytoplasm colocalizing with dynein and Notch ligand DeltaD (Dld). What drives Par-3 to the cytoplasm and its impact on RGP ACD remain unknown. Here, we visualize cytoplasmic Par-3 using in vivo time-lapse imaging and find that Ser954 of zebrafish Par-3 is phosphorylated by Aurora kinase A (AurkA) in vitro. Expression of the nonphosphorylated mutant Par-3S954A dominant negatively affects embryonic development, reduces cytoplasmic Par-3, and disrupts the anteroposterior asymmetry of cortical Par-3 and Dld endosomes and, in turn, daughter cell fate. AurkA in mitotic RGPs shows dynamic pericentrosomal distribution that transiently colocalizes with cortical Par-3 preferentially on the posterior side. AurkA is both necessary and sufficient to increase cytoplasmic while decreasing cortical Par-3, disrupts Par-3 cortical asymmetry, and perturbs polarized Dld endosome dynamics. These findings suggest that AurkA regulates Par-3 cortical-cytoplasmic dynamics that is critical for ACD and daughter cell fate.

DOI: https://doi.org/10.1126/sciadv.adq3858