bims-scepro 2026-01-25 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–01–25
eighteen papers selected by
William Grey, University of York

Mmrn1 expression defines a novel subset of hematopoietic stem cells and leukemia stem cells with great self-renewal potential.
SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming.
Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.
Streptavidin-drug conjugates streamline optimization of antibody-based hematopoietic stem cell transplant conditioning.
Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.
Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.
Early-life microbiota skews long-term gene expression and chromatin states of bone marrow hematopoietic precursors.
GMCL1 controls 53BP1 stability and modulates taxane sensitivity.
PRDM16 expression is an independent prognostic factor in AML with the double-mutant NPM1/FLT3-ITD genotype.
TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
PAC regulates endo-, and exocytosis, and lysosomal-mitochondrial stress signaling in human mast cells.
Prediction of myeloid malignant cells in Fanconi anemia using machine learning.
SIRT7 safeguards ERα proteostasis via deacetylation-dependent degradation of unliganded and misfolded receptors.
Highly effective combination of BRG1/BRM inhibitor with BET inhibitor or decitabine for high-risk MECOM-rearranged AML.
BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
Dynamic regulation of receptor-modulated endothelial NADPH oxidases.
Cell density-dependent nuclear-cytoplasmic shuttling of SETDB1 integrates with Hippo signaling to regulate YAP1-mediated transcription.

Haematologica. 2026 Jan 22.

Mmrn1 expression defines a novel subset of hematopoietic stem cells and leukemia stem cells with great self-renewal potential.

Naicheng Chen, Lijing Yang, Fang Chen, Hao Zeng, Xiaoyi Zhong, Yanying Liu, Zijin Chen, Mengying Yao, Yukai Lu, Mingqiang Shen, Mo Chen, Yang Xu, Song Wang, Xi Zhang, Junping Wang, Mengjia Hu.

Hematopoietic stem cells (HSCs) are critical for lifelong blood cell generation. After mutation accumulation and functional disruption, HSCs may transform into leukemic stem cells (LSCs), leading to malignant hematological disorders. However, both HSCs and LSCs are highly heterogeneous, which hinders our comprehensive understanding of their biological characteristics and clinical application. Here, we identified multimerin 1 (Mmrn1) as a reliable marker for the most primitive HSCs and LSCs. We found that Mmrn1 was abundantly present in human and mouse HSCs. Interestingly, HSCs with high levels of Mmrn1 displayed increased quiescence and regenerative capacity, accompanied by megakaryocytic lineage commitment. Importantly, Mmrn1 deficiency gradually impairs HSC self-renewal under stress of transplantation due to reduced quiescence. Additionally, we noticed that Mmrn1 was specifically upregulated in acute myeloid leukemia (AML) cells, and its overexpression predicted poor patient prognosis. Further investigation revealed that Mmrn1 marked a subset of quiescent LSCs responsible for AML initiation and development, and that deletion of Mmrn1 delays AML progression. Collectively, these data broaden our knowledge of stem cell heterogeneity in the context of normal and malignant hematopoiesis and advance the precision diagnosis and therapy of AML in the clinic.

DOI: https://doi.org/10.3324/haematol.2025.287609
Blood Neoplasia. 2026 Feb;3(1): 100185

SKIDA1 sustains MLL::ENL-expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming.

Jonny Mendoza-Castrejon, Wei Yang, Elisabeth Denby, Rohini Muthukumar, Emily B Casey, Riddhi M Patel, Sarah K Tasian, Jeffrey A Magee.

Infant leukemias arise as B-cell acute lymphoblastic or acute myeloid leukemia. Most are driven by chromosomal rearrangements of the MLL/KMT2A gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target genes during these early stages of life. In this study, we used a transgenic mouse model of MLL::ENL-driven leukemia to identify Skida1 as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. SKIDA1 is highly expressed in human MLLr leukemias, and the encoded protein associates with the polycomb repressive complex 2. We show that Skida1 is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells during neonatal development. Conditional deletion of Skida1 has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally restricted targets of MLL fusion proteins, such as SKIDA1, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.

DOI: https://doi.org/10.1016/j.bneo.2025.100185
Haematologica. 2026 Jan 22.

Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms.

Xiaoxi Yang, Sandy Lee, Kyla Masarik, Tameena Ahmed, Lei Zheng, Huichun Zhan.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and expansion of neoplastic hematopoietic stem cells (HSCs). Megakaryocytes (MKs) not only regulate HSC function but also shape immune responses within the marrow niche. Using an aging murine model of MPN with MK-restricted JAK2V617F expression, we investigated the immunomodulatory roles of mutant MKs. Compared to wild-type MKs, aged mutant MKs exhibit enhanced antigen uptake and MHC I presentation, secretion of pro-inflammatory cytokines (PF4, TGFβ, IL-1β), and induction of T cell dysregulation in the marrow niche. In chimeric murine models with co-existing wild-type and JAK2V617F mutant hematopoietic cells, enhanced MK immune activity correlates with mutant cell expansion and MPN development. Single-cell RNA sequencing revealed that aging amplifies JAK2V617F MK-driven immune remodeling. Notably, aged mutant MKs showed marked upregulation of LINE-1 (long-interspersed element-1) retrotransposon transcripts alongside elevated innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), implicating retrotransposon activity in niche inflammation. In human MPN marrow, immunohistochemistry detected LINE-1-encoded protein ORF1p in MKs from 12 of 13 MPN patients, but not in orthopedic controls (n=5). These findings identify MKs as active immune regulators in MPNs, with JAK2V617F mutation and aging synergizing to reprogram MKs into inflammatory, immunemodulatory niche cells. LINE-1 activation emerges as a potential driver of chronic marrow inflammation and a targetable mechanism in clonal hematopoiesis and MPN progression.

DOI: https://doi.org/10.3324/haematol.2025.288948
Blood Immunol Cell Ther. 2025 Dec;pii: 1000012. [Epub ahead of print]1(3):

Streptavidin-drug conjugates streamline optimization of antibody-based hematopoietic stem cell transplant conditioning.

Aditya R Yelamali, Ezhilarasi Chendamarai, Julie K Ritchey, Michael P Rettig, John F DiPersio, Stephen P Persaud.

  Hematopoietic stem cell transplantation (HSCT) conditioning using antibody-drug conjugates (ADC) is a promising approach to preparing patients for transplant, potentially avoiding the severe toxicities of conventional chemotherapy- and irradiation-based conditioning regimens. The toxic payload determines the efficacy and potential toxicities of an ADC, but comparison of different payloads in conjugates designed for HSCT conditioning has not been reported. Such comparisons would be greatly facilitated by methods enabling efficient screening of many combinations of antibody and payload. Herein, we used Click chemistry to conjugate four different small molecule payloads to a streptavidin backbone, yielding streptavidin-drug conjugates that can be combined with any biotinylated antibody to rapidly and cost-effectively produce an ADC. We vetted this system by evaluating CD45-targeted ADCs, finding pyrrolobenzodiazepine (PBD) dimers to be the most effective payload of those we tested for targeting mouse and human hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells. Single-dose murine CD45-PBD enabled near-complete conversion to donor hematopoiesis in syngeneic HSCT models as well as in autologous transplantation using gene-edited HSCs. Finally, human CD45-PBD targeted human HSCs in vivo and provided significant antileukemia benefit in a patient-derived AML xenograft model. Notably, our streptavidin-drug conjugates were produced using routine molecular biology techniques and readily available supplies without requiring complex instrumentation, making production and screening of ADCs for myriad targeting applications accessible to virtually any laboratory.

Keywords:  Antibody-drug conjugate; HSCT; conditioning; leukemia; streptavidin

DOI:  https://doi.org/10.1016/j.bict.2025.100012
iScience. 2026 Jan 16. 29(1): 114533

Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.

Kazuya Fukasawa, Kazuya Tokumura, Makoto Yoshimoto, Koki Sadamori, Ioanna Mosialou, Yoshiaki Harakawa, Kazuto Isawa, Shohei Tsuji, Haruhiko Inufusa, Atsushi Hirao, Stavroula Kousteni, Eiichi Hinoi.

  Acute myeloid leukemia (AML) is widely recognized for its intrinsic leukemic-cell-driven regulation as well as its extrinsic niche-driven regulation. Despite mounting evidence that bone-forming osteoblasts provide an endosteal niche for AML cells, the precise mechanism remains to be elucidated. The cell-autonomous mammalian target of rapamycin complex 1 (mTORC1) is involved in the onset and progression of AML. Here, we found that mTORC1 signaling was activated in the osteoblasts of an AML murine model and clinical AML specimens. Osteoblast-specific mTORC1 activation in mice promotes AML growth, whereas mTORC1 inactivation suppresses it. Interleukin-6 (IL-6) was identified through screening as a downstream factor in mTORC1-regulated AML progression. Genetic ablation of the IL-6 receptor in AML cells significantly attenuated AML growth in osteoblast-specific mTORC1-activated mice. Collectively, our results suggest that the mTORC1/IL-6 axis in osteoblastic niche non-autonomously contributes to the AML progression, suggesting a viable therapeutic target for AML.

Keywords:  cancer; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114533
Blood Neoplasia. 2026 Feb;3(1): 100182

Single-cell proteogenomic analysis of clonal evolution in PDX models of AML treated with IDH inhibitors.

Alex C H Liu, Severine Cathelin, Dhanoop Manikoth Ayyathan, Yitong Yang, Farzaneh Aboualizadeh, Amina Abow, Gurbaksh Basi, Lance Li, David L Dai, Abdula Maher, Eric Grignano, Mohsen Hosseini, Vivian Wang, Troy Ketela, Brandon Nicolay, Dylan M Marchione, Adriana E Tron, Andrea Arruda, Mark D Minden, Steven M Chan.

Clonal heterogeneity in acute myeloid leukemia (AML) can drive drug resistance because different clones may respond variably to treatments. Studying the evolution of these clones under the influence of therapeutic selective pressures is important for designing strategies to overcome drug resistance. Here, we used single-cell proteogenomic analysis to monitor the clonal evolution and differentiation of isocitrate dehydrogenase (IDH)-mutated AML in patient-derived xenografts (PDX) treated with IDH inhibitors alone or in combination with other antileukemic therapies. Furthermore, we generated mixed PDX models by coengrafting ≥2 leukemic samples into the same animal and used single-cell DNA sequencing to deconvolute their clonal composition. Using these models, we tracked clonal evolution under selective pressure from IDH inhibitors and combination therapies, identifying an association between WT1 mutations and ivosidenib (IDH1 inhibitor) monotherapy resistance, as well as an antagonism between ivosidenib and enasidenib (IDH2 inhibitor) when tested in IDH1-mutated cells. Our findings demonstrate how single-cell proteogenomic analysis of PDX models can illuminate drug resistance mechanisms and inform therapeutic strategies.

DOI: https://doi.org/10.1016/j.bneo.2025.100182
Cell Rep. 2026 Jan 21. pii: S2211-1247(25)01643-2. [Epub ahead of print]45(2): 116871

Early-life microbiota skews long-term gene expression and chromatin states of bone marrow hematopoietic precursors.

Ahmed K Kabil, Alissa Cait, Lisa A Reynolds, Sameeksha Chopra, Misha Bilenky, Michelle Moksa, Yicong Li, Jessica Cait, Diana Canals Hernaez, R Wilder Scott, Emily Fogarty, B Brett Finlay, William W Mohn, Martin Hirst, Michael R Hughes, Kelly M McNagny.

  Early life is a critical window during which the gut microbiota sculpts immunity and long-term susceptibility to allergic disease. Using neonatal antibiotic administration and bone marrow transplantation assays, we show that depletion of short-chain fatty acid (SCFA)-producing bacteria alters gene expression in hematopoietic stem and progenitor cells (HSPCs) and imprints a persistent, transplantable atopic immune phenotype. Bone marrow transplants from exposed mice generate recipients with elevated serum immunoglobulin E (IgE), downstream increased IgE bound to basophils, and exacerbated allergic lung inflammation following papain challenge. Depletion of SCFA-producing bacteria also impairs recovery from chemotherapy-induced myelosuppression and increases DNA damage in long-term HSPCs in an antibiotic-specific manner. Histone 3 lysine 27 (H3K27) chromatin immunoprecipitation sequencing (ChIP-seq) analyses further reveal differential histone acetylation in HSPCs, consistent with an SCFA-mediated epigenetic regulatory mechanism. Collectively, these findings establish a link between gut microbiota composition, hematopoiesis, and long-term immune function, offering a mechanistic explanation for microbiota-driven susceptibility to atopic disease and hematopoietic dysfunction.

Keywords:  CP: Microbiology; CP: Stem cell research; allergic lung inflammation; bone marrow transplant; butyrate; early-life gut microbiota; epigenome; fecal microbiota transplantation; gut microbiome; hematopoietic stem and progenitor cells; immune development; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.celrep.2025.116871
Elife. 2026 Jan 19. pii: RP106730. [Epub ahead of print]14

GMCL1 controls 53BP1 stability and modulates taxane sensitivity.

Yuki Kito, Tania J González-Robles, Sharon Kaisari, Juhee Pae, Sheena Faye Garcia, Juliana Ortiz-Pacheco, Beatrix Ueberheide, Antonio Marzio, Gergely Róna, Michele Pagano.

  Mitotic surveillance pathways monitor the duration of mitosis (M phase) in the cell cycle. Prolonged M phase, caused by spindle attachment defects or microtubule-targeting drugs, triggers formation of the ternary 'mitotic stopwatch pathway' complex (MSP) consisting of 53BP1, USP28, and p53. This complex stabilizes p53, leading to cell cycle arrest or apoptosis in daughter cells. In cancers that are resistant to paclitaxel, a microtubule-targeting agent, cells bypass mitotic surveillance activation, allowing unchecked proliferation, although the underlying mechanisms remain poorly understood. Here, we identify GMCL1 as a key negative regulator of MSP signaling. We show that 53BP1 physically interacts with GMCL1, but not its paralog GMCL2, and we map their interaction domains. CRL3GMCL1 functions as a ubiquitin ligase that targets 53BP1 for degradation during the M phase, thereby reducing p53 accumulation in daughter cells. Depletion of GMCL1 inhibits cell cycle progression upon release from prolonged mitotic arrest, a defect that is rescued by co-silencing 53BP1 or USP28. Moreover, GMCL1 depletion sensitizes cancer cells to paclitaxel in a p53-dependent manner. Together, our findings support a model in which dysregulated CRL3GMCL1-mediated degradation of 53BP1 prevents proper MSP function, leading to p53 degradation and continued proliferation. Targeting GMCL1 may, therefore, represent one possible avenue for addressing paclitaxel resistance in cancer cells with functional p53.

Keywords:  53BP1; GMCL1; cancer biology; cell biology; human; mitotic stopwatch; p53; prolonged mitosis; protein degradation

DOI:  https://doi.org/10.7554/eLife.106730
Ann Hematol. 2026 Jan 22. 105(2): 49

PRDM16 expression is an independent prognostic factor in AML with the double-mutant NPM1/FLT3-ITD genotype.

Sebastian Stasik, Jan-Niklas Eckardt, Christoph Röllig, Claudia D Baldus, Hubert Serve, Carsten Müller-Tidow, Kerstin Schäfer-Eckart, Martin Kaufmann, Stefan W Krause, Mathias Hänel, Andreas Neubauer, Gerhard Ehninger, Uwe Platzbecker, Martin Bornhäuser, Johannes Schetelig, Jan M Middeke, Christian Thiede.

  PRDM16 (PR Domain Containing 16) is a transcription factor that plays a critical role in hematopoietic stem cell maintenance. In acute myeloid leukemia (AML), PRDM16 overexpression is linked to specific cytogenetic risk groups and poor prognosis. However, in NPM1-mutated AMLs, PRDM16 expression varies widely, with no consensus on its prognostic significance. To understand molecular and clinical associations of PRDM16 expression in this relevant subgroup, we screened 503 adult NPM1-mutant AML patients. High PRDM16 expression was associated with mutations in DNMT3A (57% vs 22%; p < 0.0001) and FLT3-ITD (51% vs 37%; p = 0.0258), and therefore a higher rate of ELN2022 intermediate-risk (42% vs 26%; p = 0.01), compared to low PRDM16 expression. Accordingly, PRDM16 overexpression was not associated with clinical outcome in multivariable analysis adjusting for ELN2022 risk in the unselected NPM1-mutant AML cohort. However, within the double-mutant NPM1/FLT3-ITD subgroup (n = 200), low PRDM16 expression was an independent prognostic factor for longer survival (hazard ratio [95%-CI] 0.467 [0.270-0.807]; p = 0.006). On a molecular level, low PRDM16 expression was associated with mutations in epigenetic regulators (TET2, IDH1/2) and increased PRDM16 promoter methylation, suggesting impaired TET/IDH-mediated DNA-demethylation as underlying mechanism. Notably, IDH1 R132C and IDH2 R140Q alterations particularly contributed to higher PRDM16 promoter methylation and reduced expression. These results suggest an association of PRDM16 overexpression with the NPM1/FLT3-ITD/DNMT3A triple-mutant AML genotype, typically linked to high leukemia stem cell frequencies and poor prognosis. Importantly, within this adverse AML subtype low PRDM16 expression is an independent prognostic marker for favorable outcome, supporting an anti-leukemic mechanism in AMLs with repressed PRDM16 transcription.

Keywords:   PRDM16 expression; Acute Myeloid Leukemia (AML); Clinical Outcome; Molecular associations

DOI:  https://doi.org/10.1007/s00277-026-06767-x
Nat Commun. 2026 Jan 20.

TET1 as a master regulator controlling GPX4-dependent and -independent ferroptosis surveillance in acute myeloid leukemia.

Lingling Yang, Jun Lu, Weina Yun, Xinquan Yang, Jie Sun, Chaodong Ge, Fei Han, Xiang Li, Junxia Min, He Huang, Fudi Wang, Xi Jiang.

Ferroptosis, an iron-dependent, lipid peroxidation-driven programmed cell death, holds substantial promise for cancer therapy, yet its translational potential is hindered by widespread intrinsic resistance. While glutathione peroxidase 4 (GPX4) is a well-established ferroptosis suppressor, the epigenetic circuitry coordinating GPX4-related mechanisms remains elusive. Here, via genome-wide screening, we identify ten-eleven translocation 1 (TET1)-a key mediator of DNA 5-hydroxymethylation-as a master controller of cancer cell ferroptosis susceptibility. In acute myeloid leukemia (AML), TET1 enhances 5hmC deposition at the glutamate-cysteine ligase catalytic subunit (GCLC) promoter to activate glutathione/γ-glutamyl-peptide metabolism, fortifying GPX4-dependent defense. Concurrently, TET1 activates NFκB signaling to upregulate GTP cyclohydrolase-1 (GCH1), conferring GPX4-independent ferroptosis resistance. Critically, co-targeting TET1/GCLC/GCH1 with low-dose ferroptosis inducers exhibits potent therapeutic effects against both ferroptosis-sensitive and -resistant AML. Our work positions TET1 as a pivotal epigenetic hub governing ferroptosis surveillance, and provides a translatable strategy to overcome ferroptosis resistance in cancer, with AML as a paradigm.

DOI: https://doi.org/10.1038/s41467-026-68509-x
Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

  Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2621110
Cell Commun Signal. 2026 Jan 20.

PAC regulates endo-, and exocytosis, and lysosomal-mitochondrial stress signaling in human mast cells.

Korollus Melek, Philip Steiner, Sven Kappel, Benjamin Gottschalk, Ancuela Andosch, Michelle Duggan, Wolfgang F Graier, Susanna Zierler, Christine Peinelt.

  In mast cells, endo- and exocytotic pathways are central to the (patho)physiological release of pro-inflammatory mediators, linking intracellular signaling with immune communication. Proton-activated chloride (PAC) channel mediates acid-sensitive outwardly rectifying anion channel (ASOR/PAORAC) currents, however, its physiological functions are poorly understood.Using electrophysiology, live-cell imaging, electron microscopy, and functional assays, we investigate the role of PAC in human mast cells.We detected ASOR/PAORAC in primary human mast cells and mast cell lines and demonstrated its essential role in vesicular signaling. PAC knockout reduced vesicular pH, increased endocytosis, decreased exocytosis, and disrupted endolysosomal homeostasis. Upon activation of exocytosis, the lack of PAC reduced CD107a (LAMP-1) surface expression. PAC-deficient cells also displayed increased colocalization of lysosomes and mitochondria, elevated ROS levels, and the appearance of C-shaped mitochondria, suggesting that PAC regulates inter-organelle stress signaling. Functionally, PAC knockout impaired mitochondrial respiration, linking ion channel activity to mast cell metabolic adaptation.These findings establish PAC as a key regulator of endo- and exocytosis-dependent signaling and lysosomal-mitochondrial stress response in human mast cells, highlighting its physiological relevance and potential as a therapeutic target in mast cell-associated disorders.

Keywords:  Endocytosis; Endosomal homeostasis; Exocytosis; Lysosomal-mitochondrial stress signaling; Mast cell; PAC

DOI:  https://doi.org/10.1186/s12964-026-02661-1
PLoS One. 2026 ;21(1): e0340578

Prediction of myeloid malignant cells in Fanconi anemia using machine learning.

Luis A Flores-Mejía, Pablo Siliceo, Ulises Juárez Figueroa, Angel A De la Cruz, Cecilia Ayala-Zambrano, Hugo Tovar, Sara Frías, Alfredo Rodríguez.

Fanconi anemia (FA) is an inherited bone marrow failure syndrome with cancer predisposition. Most FA patients develop aplastic anemia during childhood and have an extremely high cumulative risk to develop cancer during their lifespan. Myeloid malignancy is one of the main neoplastic risks for patients with FA, including high-risk myelodysplastic syndrome (MDS), recently renamed as myelodysplastic neoplasm, and acute myeloid leukemia (AML). Although bone marrow transplantation is the treatment of choice for FA patients that develop aplastic anemia, patients with a more stable bone marrow remain not transplanted and at a high risk of presenting MDS/AML, these patients therefore should be monitored for appearance of myeloid malignant clones. Markers for an as-early-as-possible identification of emerging myeloid malignant cells are needed for the monitoring of patients with FA, since quick medical action after detection of neoplastic transformation is needed. In this work we have developed a deep neural network (DNN) model that was trained with publicly available single cell RNA-seq (scRNA-seq) datasets of patients with AML and used to predict the presence of AML-like cells in scRNA-seq datasets obtained from bone marrow samples of patients with FA. The predictor displayed high sensitivity, specificity, and accuracy for the detection of single-cell resolution myeloid malignant transcriptional profiles. Functional analyses of the predicted-AML cells from FA patients showed enrichment of lympho-myeloid-primed progenitor (LMPP) and granulocyte-monocyte progenitor (GMP) populations, as well as transcriptional profiles associated with malignant transformation. Cues of immune evasion were also detected using single cell pathway analysis (SCPA) and cell-cell communication profiles.

DOI: https://doi.org/10.1371/journal.pone.0340578
J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00043-8. [Epub ahead of print] 111173

SIRT7 safeguards ERα proteostasis via deacetylation-dependent degradation of unliganded and misfolded receptors.

Mengdi Cao, Junfeng Zhang, Huixia Liu, Ronghui Fan, Faliang Wu, Yitong Meng, Tiansheng Li, Yalan Wu, Xiaolong Tang.

  SIRT7 has been implicated in diverse physiological and pathological processes, yet its role in sexual dimorphism and the underlying molecular mechanisms remain insufficiently explored. Given that ERα-mediated estrogen signaling is a central regulator of sexual dimorphism and that ERα undergoes stringent quality control to preserve signaling sensitivity, we investigated whether SIRT7 and ERα are mechanistically connected. Here, we identify SIRT7 as a molecular inspector that safeguards the quality of estrogen receptor α (ERα) to fine-tune estrogen signaling through the regulation of ERα proteostasis. Under estrogen-deprived conditions or in the presence of misfolded ERα, SIRT7 deacetylates ERα and promotes its degradation through the E3 ubiquitin ligase STUB1, thereby maintaining a functional receptor pool and preserving estrogen responsiveness. During this process, deacetylated ERα competes with SIRT7 for STUB1 binding, an E3 ligase that is also required for SIRT7 protein turnover, thus leading to SIRT7 stabilization. As a feedback mechanism, upon estrogen (E2) stimulation, E2-bound ERα activates non-genomic MAPK signaling to trigger SIRT7 degradation via another E3 ligase UBR5, which ensures the proper receptor signaling activation. Given the central role of ERα in aging and hormone-related cancers, our findings highlight SIRT7 as a key regulator linking age-associated disorders and hormone-driven tumorigenesis.

Keywords:  ERα; Estrogen signaling; Protein degradation; Receptor quality control; SIRT7

DOI:  https://doi.org/10.1016/j.jbc.2026.111173
Hemasphere. 2026 Jan;10(1): e70289

Highly effective combination of BRG1/BRM inhibitor with BET inhibitor or decitabine for high-risk MECOM-rearranged AML.

Warren Fiskus, Christopher P Mill, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christine E Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Jian Wang, Sanam Loghavi, Xiaoping Su, Courtney D DiNardo, Ruud Delwel, Kapil N Bhalla.

In AML with 3q26.2 rearrangements (r) the distal GATA2 hematopoietic enhancer becomes aberrantly relocated leading to activation of EVI1 expression. EVI1 is a transcriptional regulator that plays a role in proliferation and maintenance of a stem cell-like phenotype in AML. BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive ATPases of the BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. They regulate access to enhancers/promoters and gene-expressions orchestrating AML stem/progenitor cell proliferation and differentiation. AML with 3q26.2 rearrangements are clinically challenging and prognosis remains very poor. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induced differentiation and lethality in AML cells with MECOM-r, perturbed chromatin accessibility and depleted expression of EVI1, c-Myc, CD44 and CDK4. Co-treatment with FHD-286 and decitabine, BET inhibitor (BETi) or HAT inhibitor synergistically induced in vitro lethality in patient-derived AML cells with MECOM-r. In patient-derived xenograft (PDX) models of AML with MECOM-r, compared to each drug alone, co-treatment with FHD-286 and BETi OTX015 significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with chromosome 3q26.2 rearrangement and EVI1 overexpression.

DOI: https://doi.org/10.1002/hem3.70289
Ann Hematol. 2026 Jan 19. 105(1): 32

BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.

Florian Robert, Cherif Badja, Soraya Boushaki, Andrea Degasperi, Yasin Memari, Sophie Momen, Theodoros I Roumeliotis, Zuza Kozik, Malgorzata Gozdecka, Jyoti Choudhary, George Vassiliou, Gene Cc Koh, Serena Nik-Zainal.

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH's role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

Keywords:  Acute myeloid leukemia; BCOR; DHODH; DHODH inhibition; Leukemia; Synthetic lethality; Targeted therapy

DOI:  https://doi.org/10.1007/s00277-026-06773-z
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2531380123

Dynamic regulation of receptor-modulated endothelial NADPH oxidases.

Markus Waldeck-Weiermair, Apabrita A Das, Taylor A Covington, Jennifer L Meitzler, James H Doroshow, Junyi Duan, Yick W Fong, Jonas Kaynert, Shambhu Yadav, Tanoy Dutta, Fotios Spyropoulos, Arvind K Pandey, Thomas Michel.

  The stable reactive oxygen species (ROS) hydrogen peroxide (H2O2) acts as a key signaling molecule for many vital intracellular pathways. In diverse cell types, surface receptors control intracellular H2O2 levels by modulating the activity of NADPH oxidases (NOX), a family of enzymes responsible for ROS synthesis. Most NOX isoforms are regulated through the reversible assembly of protein subunits to form an active oligomeric complex. The NOX isoforms NOX2 and NOX4 are expressed in endothelial cells and generate H2O2 in response to activation of cell surface receptors. The GPCR agonist histamine activates NOX2 independently of NOX4, but the H2O2 response to activation of the receptor tyrosine kinase agonist vascular endothelial growth factor (VEGF) involves both NOX2 and NOX4 by unknown mechanisms [M. Waldeck-Weiermair et al., Redox Biol. 58, 102539 (2022); M. Waldeck-Weiermair et al., Redox Biol. 73, 103214 (2024)]. Here, we show that endothelial NOX4 is localized to the endoplasmic reticulum (ER). We define the redox states of various subcellular locales in the vascular endothelium and demonstrate that NOX2 is responsible for cytosolic H2O2 signaling, whereas NOX4 contributes to H2O2 generation in the endoplasmic reticulum. Using biochemical assays and structural modeling, we further identify a previously unrecognized regulatory interaction in which the NOX2 subunit p67 associates with NOX4. VEGF stimulation induces dynamic dissociation of p67 from NOX4, unveiling a "cross talk" between NOX isoforms that coordinates the activation of both NOX2 and NOX4 and thereby produces compartment-specific H2O2 signals. This mechanism underscores the pivotal roles of NOX2 and NOX4 subunit interactions in endothelial redox homeostasis controlling cell survival, proliferation, and migration.

Keywords:  NADPH oxidase; endothelial cell signaling; hydrogen peroxide

DOI:  https://doi.org/10.1073/pnas.2531380123
FEBS Lett. 2026 Jan 19.

Cell density-dependent nuclear-cytoplasmic shuttling of SETDB1 integrates with Hippo signaling to regulate YAP1-mediated transcription.

Jaemin Eom, Jaewoong Jang, Jung Sun Park, Yong-Kook Kang.

  SETDB1, a H3K9 methyltransferase involved in nuclear transcriptional silencing, also localizes to the cytoplasm through unclear mechanisms. Here, we identify cell density as key regulator of SETDB1 subcellular localization and demonstrate its role in modulating the Hippo signaling pathway. Under low-density culture, SETDB1 distributes between nucleus and cytoplasm, whereas high-density culture triggers nuclear exclusion and proteasomal degradation. SETDB1 depletion reduces YAP1 phosphorylation and increases nuclear YAP1 accumulation. Transcriptomic analysis of SETDB1 knockout cells revealed upregulation of YAP1-TEAD1 target genes (YTGs). Immunoprecipitation experiments showed that SETDB1 is recruited to YTG promoters via TEAD1 and competes with YAP1 for TEAD1 binding. These findings reveal that SETDB1 regulates Hippo pathway output through YAP1 phosphorylation modulation and competitive transcriptional repression.

Keywords:  ATF7IP; Hippo pathway; TEAD; phosphorylation; proteasomal degradation

DOI:  https://doi.org/10.1002/1873-3468.70286