bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–11–09
twenty-one papers selected by
William Grey, University of York
  1. Dynamic activity of Erg promotes maturation of the hematopoietic system.
  2. A novel strategy to target metabolic dependencies in acute myeloid leukemia.
  3. Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
  4. Novel humanized loss-of-function NF1 mouse model of juvenile myelomonocytic leukemia.
  5. Dynamic rRNA Methylation Regulates Translation in the Hematopoietic System and is Essential for Stem Cell Fitness.
  6. Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.
  7. GAB2 couples genetic drivers and signaling networks in acute myeloid leukemia.
  8. Tandem duplications in UBTF create XPO1-dependent nuclear export signals that reveal a leukemic therapeutic dependency.
  9. Disparate leukemia mutations converge on nuclear phase-separated condensates.
  10. Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy.
  11. Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome.
  12. Setd2 ensures the establishment of a precise basal inflammatory state within murine hematopoietic stem/progenitor cells.
  13. PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.
  14. Human B-lymphopoiesis: Clinical challenges in B cell reconstitution and advances in in vitro modeling.
  15. CD43, but not CD41 or GPI-80, marks first definitive haematopoietic stem cells in the human embryo.
  16. Innate immune-inflammatory signaling milieu in myeloid leukemia and aging-associated clonal hematopoiesis pathologies.
  17. PIKfyve inhibition in myeloma disrupts autophagy and the lysosome, increasing MHC expression and cholesterol metabolism.
  18. Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
  19. Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.
  20. Advanced Multicolor Flow Cytometry Method for Multiple Myeloma.
  21. "Connexin" the dots in hematopoietic stem cell potential.
  1. Blood Adv. 2025 Nov 05. pii: bloodadvances.2025017705. [Epub ahead of print]
    Dynamic activity of Erg promotes maturation of the hematopoietic system.
    Mayuri Tanaka-Yano, Wade Sugden, Dahai Wang, Marcelo Falchetti, Brianna Badalamenti, Parker Côté, Diana H Chin, Julia Goldstein, Stephan George, Gabriela Flavia Rodrigues-Luiz, Edroaldo Lummertz da Rocha, Hojun Li, Trista North, Berkley E Gryder, Robert Grant Rowe.
      Hematopoiesis changes over the lifetime to adapt to the physiology of development, maturation, and aging. Temporal changes in hematopoiesis parallel age-dependent incidences of certain blood diseases. Several heterochronic regulators of hematopoiesis have been identified, but how the master transcription factor (TF) circuitry of definitive hematopoietic stem cells (HSCs) adapts to changes in physiology over the lifespan is unknown. Here, we show that programmed upregulation of expression of the ETS family TF Erg during prenatal to adult maturation is evolutionarily conserved and required for implementation of adult patterns of HSC self-renewal and myeloid, erythroid, and lymphoid differentiation. Erg deficiency maintains fetal transcriptional and epigenetic programs in adulthood, and persistent juvenile phenotypes in Erg haploinsufficient mice are at least in part dependent on deregulation of the fetal-biased factor Hmga2. Overall, we identify a mechanism whereby master HSC TF networks are rewired to specify stage-specific hematopoiesis, a finding directly relevant to age-biased blood diseases.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017705
  2. Cell Death Dis. 2025 Nov 04. 16(1): 792
    A novel strategy to target metabolic dependencies in acute myeloid leukemia.
    Nithya Balasundaram, Hamenth Kumar Palani, Arvind Venkatraman, Yolanda Augustin, Shruthi Pichandi, Clement Regnault, Majeela Solomon, Abirami Rajasekaran, Mohammed Yasar, Swathy Palani Kumar, Reeshma Nair Radhakrishnan, Anu Korula, Uday Prakash Kulkarni, Eunice Sindhuvi Edison, Poonkuzhali Balasubramanian, Biju George, Aby Abraham, Sanjeev Krishna, Vikram Mathews.
      Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.
    DOI:  https://doi.org/10.1038/s41419-025-08129-3
  3. Blood. 2025 Nov 05. pii: blood.2025030209. [Epub ahead of print]
    Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells.
    Gentaro Kawano, Riichiro Ikeda, Daisuke Ishihara, Takahiro Shima, Teppei Sakoda, Shunsuke Yamamoto, Yu Kochi, Yuichiro Semba, Sanae Ashitani, Yasuo Mori, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Tomoyoshi Soga, Koichi Akashi, Yoshikane Kikushige.
      Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.
    DOI:  https://doi.org/10.1182/blood.2025030209
  4. Blood Adv. 2025 Nov 07. pii: bloodadvances.2024015191. [Epub ahead of print]
    Novel humanized loss-of-function NF1 mouse model of juvenile myelomonocytic leukemia.
    Roshani Sinha, Rachana V Patil, Rosa Romano, Devesh Sharma, Esmond Lee, Rhonda Perriman, Saori Takeda, Benjamin J Lesch, Zhenyu Yao, Y Lucy Liu, M Kyle Cromer, Matthew H Porteus, Alice Bertaina.
      Juvenile myelomonocytic leukemia (JMML) is a fatal pediatric cancer characterized by classical features such as splenomegaly, monocytosis, and GM-CSF hypersensitivity, with RAS pathway mutations being the major drivers. Mutations causing loss-of-function of the Neurofibromin1 gene (NF1LOF) occur in ~20% of JMML patients. NF1LOF drives upregulation of RAS/MAPK/PI3K pathways that lead to aggressive proliferation/differentiation of immature myeloid cells. Hematopoietic stem cell transplantation is the only curative option, but relapse occurs in ~50% of patients, indicating an urgent need for novel and targeted therapeutic strategies. However, low patient sample availability and a lack of reliable disease models have made it difficult to study and treat JMML. Using CRISPR/Cas9, we have generated NF1LOF in human umbilical cord blood-derived hematopoietic stem and progenitor cells (HSPCs). We achieved a high gene knockout rate of ~89% and concomitant loss of NF1 protein in the modified HSPCs. Importantly, NF1LOF cells displayed marked GM-CSF hypersensitivity in in vitro colony-forming unit assays - mirroring JMML; when transplanted into NSG-SGM3 mice, they caused rapid lethality, (median survival of 32 days), myeloid expansion, tissue infiltration (spleen, liver, and lungs), and specific upregulation of RAS/MAPK pathway and STAT5 genes, consistent with patient profiles. This first humanized NF1LOF mouse model recapitulates key JMML features, enabling investigation of disease mechanisms and targeted therapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015191
  5. Blood. 2025 Nov 05. pii: blood.2024028300. [Epub ahead of print]
    Dynamic rRNA Methylation Regulates Translation in the Hematopoietic System and is Essential for Stem Cell Fitness.
    Ofri Rabany, Sivan Ben Dror, Maram Arafat, Hadar Aharoni Levitanus, Yudit Halperin, Virginie Marchand, Nikolai Romanovski, Noga Ussishkin, Maayan Livneh Golany, Adi Reches, Judith Wexler, Nina Mayorek, Galya Monderer-Rothkoff, Sagiv Shifman, Widad Mâmmer Bouhou, Michael VanInsberghe, Cornelius Pauli, Carsten Müller-Tidow, Ola Karmi, Yoav Livneh, Alexander van Oudenaarden, Yuri Motorin, Daphna Nachmani.
      Self-renewal and differentiation are at the basis of hematopoiesis. While it is known that tight regulation of translation is vital for hematopoietic stem cells' (HSCs) biology, the mechanisms underlying translation regulation across the hematopoietic system remain obscure. Here we reveal a novel mechanism of translation regulation in the hematopoietic hierarchy, which is mediated by ribosomal RNA (rRNA) methylation dynamics. Using ultra-low input ribosome-profiling, we characterized cell-type-specific translation capacity during erythroid differentiation. We found that translation efficiency changes progressively with differentiation and can distinguish between discrete cell populations as well as to define differentiation trajectories. To reveal the underlying mechanism, we performed comprehensive mapping of the most abundant rRNA modification - 2'-O-methyl (2'OMe). We found that, like translation efficiency, 2'OMe dynamics followed a distinct trajectory during erythroid differentiation.Genetic perturbation of individual 2'OMe sites demonstrated their distinct roles in modulating proliferation and differentiation. By combining CRISPR screening, molecular and functional analyses, we identified a specific methylation site, 28S-Gm4588, which is progressively lost during differentiation, as a key regulator of HSC self-renewal. We showed that low methylation at this site led to translational skewing, mediated mainly by codon frequency, which promoted differentiation. Functionally, HSCs with diminished 28S-Gm4588 methylation exhibited impaired self-renewal capacity ex-vivo, and loss of fitness in-vivo in bone marrow transplantations.Extending our findings beyond the hematopoietic system, we also found distinct dynamics of 2'OMe profiles during differentiation of non-hematopoietic stem cells. Our findings reveal rRNA methylation dynamics as a general mechanism for cell-type-specific translation, required for cell function and differentiation.
    DOI:  https://doi.org/10.1182/blood.2024028300
  6. Haematologica. 2025 Nov 06.
    Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixed-lineage leukemia and mutated nucleophosmin-1.
    Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva.
      Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and BH3 profiling. Treatment with DS-1594b and venetoclax exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the NPM1-mutated AML PDX model, DS- 1594b single-agent treatment significantly extended survival. Importantly, compared with DS- 1594b monotherapy, the combination of DS-1594b and venetoclax more profoundly reduced leukemic burden and prolonged mouse survival. Menin inhibition was the primary driver of transcription changes in this model and impacted the expression of antiapoptotic regulators, providing a mechanistic explanation for the synergy observed between these drugs. Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.
    DOI:  https://doi.org/10.3324/haematol.2024.286833
  7. J Clin Invest. 2025 Nov 03. pii: e198684. [Epub ahead of print]135(21):
    GAB2 couples genetic drivers and signaling networks in acute myeloid leukemia.
    Amanda Luvisotto, Lu Wang.
      In acute myeloid leukemia (AML), leukemogenesis is typically driven by the sequential acquisition of distinct classes of mutations that collaborate to transform normal hematopoietic stem and progenitor cells. The founding and cooperating mutations in AML are often in signaling genes and form functional partnerships with each other, each addressing complementary aspects of malignant transformation. In this issue of the JCI, Kramer et al. elaborate on the molecular pathogenesis of AML. By using a mouse bone marrow model bearing the common AML-initiating mutations in DNA methyltransferase 3 α (DNMT3A) and nucleophosmin 1 (NPM1), the work provides further evidence for the role of the signaling orchestrator GRB2-associated-binding protein 2 (GAB2) in AML progression, positioning GAB2 as a potential therapeutic target.
    DOI:  https://doi.org/10.1172/JCI198684
  8. Blood Cancer Discov. 2025 Nov 03.
    Tandem duplications in UBTF create XPO1-dependent nuclear export signals that reveal a leukemic therapeutic dependency.
    Juan M Barajas, Aaron H Phillips, Jina Wang, Melvin E Thomas, Lisett Contreras, Masayuki Umeda, Ryan Hiltenbrand, Elizabeth Caldwell, Michael P Walsh, Guangchun Song, Lauren Ezzell, Kelly Churion, Tamara Westover, Emily Xiong, Chandra Rolle, Jamila Moore, Josi Lott, Sandi Radko-Juettner, Amit Kumar, Wenjie Qi, Beisi Xu, Evangelia K Papachristou, Clive S D'Santos, Jing Ma, Burgess B Freeman, Laura J Janke, Richard W Kriwacki, Jeffery M Klco.
      UBTF tandem duplications (UBTF-TDs) define a high-risk molecular subtype of acute myeloid leukemia (AML). While menin inhibitors show therapeutic promise in UBTF-TD AMLs, acquired resistance remains a challenge. Here, we used proteomic, epigenetic, and functional analyses to uncover mechanisms underlying UBTF-TD leukemogenesis. Biochemical studies showed that UBTF-TDs result in structural destabilization and create nuclear export signal (NES) motifs, which mediate direct interactions with XPO1. In cord-blood CD34+ UBTF-TD models, these interactions were shown to drive aberrant chromatin binding and transcriptional activation of genes dysregulated in UBTF-TD tumors. Through mutagenesis, we demonstrated that these NES motifs are critical for localization of UBTF-TD proteins to chromatin, transcriptional dysregulation, cellular proliferation, and differentiation. In preclinical UBTF-TD models of human leukemia, we found that XPO1 inhibition disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation. These mechanistic findings highlight XPO1 inhibition as a potential therapy for UBTF-TD AMLs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0112
  9. Cell. 2025 Nov 04. pii: S0092-8674(25)01149-3. [Epub ahead of print]
    Disparate leukemia mutations converge on nuclear phase-separated condensates.
    Gandhar K Datar, Elmira Khabusheva, Archish Anand, Joshua Beale, Marwa Sadek, Chun-Wei Chen, Evdokiia Potolitsyna, Nayara Alcantara-Contessoto, Guangyuan Liu, Josephine De La Fuente, Christina Dollinger, Anna Guzman, Alejandra Martell, Katharina Wohlan, Abhishek Maiti, Nicholas J Short, S Stephen Yi, Vibeke Andresen, Bjørn Tore Gjertsen, Brunangelo Falini, Rachel E Rau, Lorenzo Brunetti, Nidhi Sahni, Margaret A Goodell, Joshua A Riback.
      During cancer development, mutations promote changes in gene expression that cause transformation. Leukemia associated with aberrant HOXA expression is driven by translocations of nucleoporin genes or KMT2A as well as mutations in NPM1. The mechanistic convergence of these disparate mutations remains elusive. Here, we demonstrate that mutant nucleophosmin 1 (NPM1c) forms nuclear condensates in human cell lines, mouse models, and primary patient samples. We show NPM1c phase separation is necessary and sufficient to recruit NUP98 and KMT2A to condensates. Through extensive mutagenesis and pharmacological destabilization of phase separation, we find that NPM1c condensates are necessary for regulating gene expression, promoting in vivo leukemic expansion, and maintaining the undifferentiated leukemic state. Finally, we show that nucleoporin and KMT2A fusion proteins form condensates that are biophysically indistinguishable from NPM1c condensates. Together, these data define a new condensate that we term the coordinating body (C-body) and establish C-bodies as a therapeutic vulnerability in leukemia.
    Keywords:  AML; HOX; KMT2A; MENIN; NPM1; NUP98; XPO1; acute myeloid leukemia; condensate; phase separation
    DOI:  https://doi.org/10.1016/j.cell.2025.10.010
  10. Blood. 2025 Nov 05. pii: blood.2024027948. [Epub ahead of print]
    Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy.
    Sven Turkalj, Felix A Radtke, Bilyana Stoilova, Rabea Mecklenbrauck, Angus J Groom, Niels Asger Jakobsen, Curtis A Lachowiez, Marlen Metzner, Batchimeg Usukhbayar, Mirian Angulo Salazar, Zhihong Zeng, Sanam Loghavi, Jennifer Marvin-Peek, Verena Körber, Farhad Ravandi, Ghayas C Issa, Tapan M Kadia, Vasiliki Symeonidou, Anne P de Groot, Hagop M Kantarjian, Koichi Takahashi, Marina Konopleva, Courtney D DiNardo, Paresh Vyas.
      Acquired resistance to targeted, non-intensive therapies is common in myeloid malignancies. However, the kinetics of selection, the hematopoietic cell compartments where selection occurs, and the molecular mechanisms underlying selection remain open questions. To address this, we studied the kinetics of clonal and transcriptional responses to ivosidenib + venetoclax ± azacitidine combination therapy across hematopoiesis in 8 patients with IDH1-mutant myeloid malignancy. All 8 patients initially responded to treatment but 6 relapsed while 2 remained in sustained remission for >4 years. We performed combined high-sensitivity single-cell (sc) genotyping and scRNA-seq in index-sorted sequential patient samples. In all patients, clonal selection occurred rapidly, within 1-3 treatment cycles. Clonal selection preceded treatment failure by months to years. Relapse was associated with expansion of either clones harboring newly-detected myeloid driver mutations or pre-existing minor clones that underwent differentiation delay upon treatment exposure. In both cases, clonal selection occurred within immature cell populations previously shown to contain leukemic stem cell (LSC) potential. Different genetic alterations within relapse-associated clones converged onto common upregulated transcriptional programs of stemness, branched-chain amino acid catabolism, and genes sensitive to menin inhibition. Importantly, this relapse-associated transcriptional signature was selected within 3 cycles of therapy. In contrast, in both patients remaining in remission, leukemic clones were rapidly eradicated and replaced by clonal and wild-type hematopoiesis. Overall, in patients treated with ivosidenib combination therapy, rapid clonal selection occurs within the first treatment cycles. In those patients destined to relapse, genetically heterogeneous resistant clones are characterized by common transcriptional programs.
    DOI:  https://doi.org/10.1182/blood.2024027948
  11. Nature. 2025 Nov 03.
    Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome.
    Varun K Narendra, Tandrila Das, Linsey J Wierciszewski, Rebecca J Londoner, Joshua K Morrison, Pia Martindale, Tessa Devine, Kevin Chen, Michael Trombetta, Yuzuka Kanno, Alejandro E Casiano, Elisa de Stanchina, Caleb A Lareau, Scott W Lowe, Alexander D Gitlin.
      Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown. Here, we employ somatic gene editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. In contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-Caspase-8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link VEXAS pathogenesis with that of rarer monogenic autoinflammatory syndromes; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and support therapeutic targeting of the inflammatory cell death axis in VEXAS.
    DOI:  https://doi.org/10.1038/s41586-025-09815-0
  12. Cell Death Dis. 2025 Nov 06. 16(1): 799
    Setd2 ensures the establishment of a precise basal inflammatory state within murine hematopoietic stem/progenitor cells.
    Hong Tao, Xinyue Luo, Jiachun Song, Fuhui Wang, Yinyin Xie, Rong Fan, Xiaojian Sun, Qiuhua Huang, Yuanliang Zhang.
      The maintenance of a basal immunoinflammatory signature in hematopoietic stem/progenitor cells (HSPCs) constitutes a fundamental regulatory axis governing hematopoietic competence and immune effector generation. While epigenetic repressors constrain this inflammatory phenotype, the molecular amplifiers that preserve this critical state remain undefined. Through integrated single-cell transcriptomic/epigenomic profiling and functional interrogation, we identify Setd2-mediated H3K36me3 as an indispensable epigenetic amplifier sustaining baseline inflammation in murine HSPCs. Setd2 ablation specifically eliminated interferon (IFN)-enriched HSPC subpopulations and attenuated inflammatory signaling cascades. Functionally, Setd2-deficient HSPCs exhibited impaired IFNγ responsiveness, compromised B-lymphopoiesis, and diminished reconstitution capacity due to Lin-c-Kit+Sca1high cell depletion. Paradoxically, Setd2 loss conferred resistance to IFNγ-induced HSPCs exhaustion, which may contribute to the maintenance of Setd2-deficient HSPCs in our myelodysplastic syndrome (MDS) model under the inflammatory milieu. Mechanistically, Setd2 sustained chromatin accessibility and enhancer (H3K27ac) activity at inflammatory gene loci. This work delineates a critical link between Setd2-mediated chromatin regulation, baseline inflammation, HSPC function, and immune competence, providing insights into inflammatory dysregulation in hematopoietic malignancies like MDS.
    DOI:  https://doi.org/10.1038/s41419-025-08110-0
  13. Nat Commun. 2025 Nov 06. 16(1): 9805
    PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.
    Andrew D Huber, Wenwei Lin, Young-Hwan Jung, Shyaron Poudel, Guangwei Yang, Jing Wu, Annalise G Carrigan, Vishwajeeth Pagala, Wei Wang, Yingxue Fu, Zuo-Fei Yuan, Stephanie D Byrum, Ka Yang, Rebecca R Florke Gee, Elizabeth D Arnold, Allister J Loughran, Jingheng Wang, Shondra M Pruett-Miller, Junmin Peng, Taosheng Chen.
      Proteolysis-targeting chimeras (PROTACs) containing a target protein ligand linked to an E3 ubiquitin ligase ligand induce target protein degradation through E3 recruitment. Most PROTACs bind a surface cleft of the protein of interest rather than a buried pocket. Using the nuclear receptor PXR, we previously described the inherent difficulties of PROTAC targeting via a deep solvent-inaccessible ligand binding pocket. Here, we discover that the CRBN-dependent MDM2 PROTAC MD-224 is a potent PXR degrader that achieves its activity from binding adjacent to the ligand-binding pocket. Furthermore, because the proximal region is a structural feature common among nuclear receptors, MD-224 also targets additional receptors for proteasomal degradation. Using structure- and activity-guided medicinal chemistry, we ablated MDM2 degradation and generated MD-224 analogs with activities skewed toward different receptors. Thus, we describe (1) PROTAC repurposing as a potential route of degrader discovery and (2) nuclear receptor-targeted degradation through a noncanonical binding site.
    DOI:  https://doi.org/10.1038/s41467-025-64773-5
  14. Immunol Lett. 2025 Nov 03. pii: S0165-2478(25)00139-7. [Epub ahead of print] 107106
    Human B-lymphopoiesis: Clinical challenges in B cell reconstitution and advances in in vitro modeling.
    Franziska Maria Schmidt, Marta Rizzi.
      The B cell compartment is maintained by continuous replenishment from hematopoietic stem cells (HSCs) and multipotent progenitors, as well as from B cell precursors. B cell depletion is a common therapeutic approach, not only in the context of B cell malignancies, but also in autoimmunity. The targeted elimination of B cells can be achieved through the use of chimeric antigen receptor (CAR)-T cells or monoclonal antibodies or bispecific antibodies that target both B and NK cells or B and T cells. When B cells are depleted, repopulation from bone marrow precursors occurs within three months to one year, following ontogeny. Nevertheless, prolonged B cell aplasia is observed in some patients and is associated with a progressive reduction of serum immunoglobulins and an increased susceptibility to infections. The mechanisms underlying such defects in B cell replenishment remain to be fully elucidated and studies on human B lymphopoiesis are needed in this context. Mouse models can be helpful in studying mechanisms of B cell development and the role of multiple (B cell-specific) genes in this process; however, they do not always mirror the human developmental dynamics and signals. Hence further tools are needed to study human B lymphopoiesis defects. In this review, we summarize the reported studies and cases of prolonged B cell aplasia following B cell depletion and discuss potential underlying causes. We then provide a comprehensive overview of the various in vitro models that can be used to study the dynamic of B lymphopoiesis to dissect B cell developmental defects in humans.
    Keywords:  B lymphocytes; BM; feeder-free; iPSCs culture; in vitro; modelling; reconstitution
    DOI:  https://doi.org/10.1016/j.imlet.2025.107106
  15. Development. 2025 Nov 06. pii: dev.205108. [Epub ahead of print]
    CD43, but not CD41 or GPI-80, marks first definitive haematopoietic stem cells in the human embryo.
    A Ivanovs, S Rybtsov, N Nnadi, A Fayon, S Gordon-Keylock, D Paruzina, R A Anderson, M Tavian, A Medvinsky.
      During mammalian embryonic development, haematopoietic stem cells (HSCs) first emerge in the aorta-gonad-mesonephros (AGM) region. Human definitive HSCs emerge in low numbers and reside within the VE-CAD+CD45+ population consisting of 500-1000 cells. Accurate identification of the first HSCs emerging within this population is important for understanding their biology and underlying developmental mechanisms. Here, we characterised the expression of potential markers labelling HSCs during their emergence in the AGM at Carnegie stages (CS) 14-17. We found that the first definitive HSCs are marked by CD43, but not CD41, similar to the early haematopoietic progenitor cells differentiating in culture from human ES cells. We show that, during development in the AGM region and in the beginning of liver colonisation, HSCs remain GPI-80 negative, in contrast to liver HSCs at the later midtrimester foetal development. Together with our previous observations, these findings provide firm evidence that HSCs colonise human embryonic liver at CS17-18.
    Keywords:  AGM region; Dorsal aorta; Haematopoietic stem cell; Human embryo
    DOI:  https://doi.org/10.1242/dev.205108
  16. Front Immunol. 2025 ;16 1660709
    Innate immune-inflammatory signaling milieu in myeloid leukemia and aging-associated clonal hematopoiesis pathologies.
    Satyaki Bhowmik, Anwesha Bose, Amitava Sengupta.
      Age-related accumulation of somatic mutations in hematopoietic stem and progenitor cells (HSPCs), causing clonal hematopoiesis (CH), often precedes the development of hematologic malignancies. Chronic inflammation and aberrant cytokine expression that are common in aging, contribute to clonal expansion and genomic instability. Acute myeloid leukemia (AML) is an (epi)genetically and physiologically diverse malignancy, characterized by clonal proliferation and incomplete differentiation of HSPCs. The innate immune system, with pattern recognition receptors (PRRs), plays a pivotal role in maintaining hematopoietic homeostasis. Dysregulated signaling through PRRs disrupts hematopoiesis, fostering malignant cell proliferation. In addition, cytokines and interferons exert multifaceted effects on HSPCs, impacting their proliferation, differentiation, and survival. Therapeutic approaches targeting innate immune pathways, offer promising avenues for treating hematologic malignancies. Understanding the intricate crosstalk between innate immunity and hematopoiesis would provide insights into novel therapeutic strategies for combating hematologic malignancies, offering hope for improved patient outcomes and survival. In this review, we discuss about the malfunctioning innate immune-inflammatory axes in the context of abnormal hematopoiesis and the therapeutic approaches that are utilizing/targeting these pathways with efficacy. This review delves into the derangements of innate immune and inflammatory pathways implicated in the development of AML and myelodysplastic syndromes (MDS), shedding light on the therapeutic strategies targeting these pathways.
    Keywords:  acute myeloid leukemia; cytokines; hematopoiesis; inflammation; innate immunity; interferon signaling; mutation; pattern recognition receptors
    DOI:  https://doi.org/10.3389/fimmu.2025.1660709
  17. Blood. 2025 Nov 05. pii: blood.2025030061. [Epub ahead of print]
    PIKfyve inhibition in myeloma disrupts autophagy and the lysosome, increasing MHC expression and cholesterol metabolism.
    Cecilia Bonolo De Campos, Ruijuan He, Tessa Josephine Pelino, Dor David Abelman, Zhihua Li, Daniel K C Lee, Ding Yan Wang, Michael St Paul, Jeffrey Bruce, Craig D Simpson, Leanne Wybenga-Groot, Michael F Moran, Rodger E Tiedemann, Trevor Pugh, Tak W Mak, Olga Issakova, Nikolai Sepetov, Suzanne Trudel, A Keith Stewart.
      We previously reported a chemo-genomics screen that unexpectedly identified Phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) as a vulnerable target in multiple myeloma (MM). PIKfyve is an essential regulator of lysosomal function and autophagy. Given the high basal necessity of autophagy in MM for sustainable immunoglobulin synthesis, targeting autophagy holds clinical potential as a novel therapeutic avenue. Here, we report the development and characterization of PIK001 and analogues, potent and selective novel small-molecule inhibitors of PIKfyve. PIK001 demonstrated potent anti-MM activity in vitro, as well as synergistic activity with established anti-MM agents (including venetoclax and selinexor), while retaining efficacy in lenalidomide-resistant models. Multi-omic characterization of isogenic cell lines sensitive / resistant to PIK001 identified a catalytic domain mutation (PIKFYVEN1939K) and heterogenous alterations in autophagy capabilities. Importantly, we noted that PIK001 exposure also resulted in significantly increased cholesterol metabolism and upregulation of MHC Class I expression, with potential implications in tumor immunity. Beyond MM, PIKfyve inhibition also shows selective cytotoxicity in acute myeloid leukemia, melanoma, and renal cancer, highlighting broader therapeutic potential. These findings establish PIKfyve inhibition as a valid target for MM and other hematologic malignancies, provide insights into mechanisms of sensitivity and resistance, and a compelling foundation for further pre-clinical (particularly with respect to the role of cholesterol metabolism and tumor immunity) and clinical development.
    DOI:  https://doi.org/10.1182/blood.2025030061
  18. Nature. 2025 Nov 05.
    Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
    Heejun Choi, Ya-Cheng Liao, Young J Yoon, Jonathan Grimm, Nan Wang, Luke D Lavis, Robert H Singer, Jennifer Lippincott-Schwartz.
      The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.
    DOI:  https://doi.org/10.1038/s41586-025-09718-0
  19. Cell Stem Cell. 2025 Nov 03. pii: S1934-5909(25)00373-X. [Epub ahead of print]
    Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.
    Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S Mansfield, Lindsay M LaFave, Tien Peng.
      Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.
    Keywords:  cancer-associated fibroblasts; lung adenocarcinoma; p16(INK4a); senescence; senolytics; spatial transcriptomics; tumor cell plasticity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.stem.2025.10.005
  20. Clin Lymphoma Myeloma Leuk. 2025 Oct 01. pii: S2152-2650(25)04225-9. [Epub ahead of print]
    Advanced Multicolor Flow Cytometry Method for Multiple Myeloma.
    Noa Ofir, Ety Rozenberg, Omri Sharabi, Miri Zektser, Ory Rouvio, Roi Gazit.
       BACKGROUND: Multiple myeloma (MM) is a bone marrow plasma cells malignancy. Despite impressive advancements of treatments, MM remains incurable due to complex clonality. Here, we present a novel 14-color flow cytometry (FACS) protocol for robust detection and visualization of MM clonality.
    METHOD: We developed a single-tube 14-color FACS protocol to analyze fresh bone marrow samples, tested on 8 MM patients. A premixed, stable antibody cocktail was used to enhance reproducibility and streamline workflow. Dimensionality reduction technique (t-SNE) was applied to visualize plasma cell clonality.
    RESULTS: Our panel shown CD38+ CD138+ plasma cells, and their clonality. As expected, MM patients had unique clonal patterns with significant heterogeneity at primary diagnosis. Advanced t-SNE analysis provides a convenient visualization of multi-parameter heterogeneity in a unified 2-D plot. Importantly, our data presents some similarities among patients, and further differences between primary analysis and secondary relapse.
    CONCLUSIONS: Taken together, our protocol provides a robust and efficient method for improving MM diagnosis using commercially available antibodies and a standard FACS machine. Concise visualization of multi-parameter FACS will help therapeutic decisions and advance the personalized treatment strategies with emerging antigen-specific drugs.
    Keywords:  Clonality; FACS; Heterogeneity
    DOI:  https://doi.org/10.1016/j.clml.2025.09.014
  21. Blood. 2025 Nov 06. 146(19): 2276-2277
    "Connexin" the dots in hematopoietic stem cell potential.
    Larry L Luchsinger.
      
    DOI:  https://doi.org/10.1182/blood.2025030225
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