bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–10–12
sixteen papers selected by
William Grey, University of York
  1. A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
  2. Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
  3. Microvesicles secreted by CoCl2-primed mesenchymal stromal cells boost the functionality of hematopoietic stem cells cultured with them.
  4. MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia.
  5. Lineage bias in hematopoietic stem cells: more niche or intrinsic factors?
  6. Ablation of CD38 in Multiple Myeloma Cells Leads to an Aggressive Phenotype in a Mouse Xenograft Model.
  7. Induced pluripotent stem cell-based modelling of disease evolution in myeloid leukemia: MDS to AML.
  8. Large-scale generation of iNK and CAR-iNK cells from CD34+ haematopoietic stem and progenitor cells for adoptive immunotherapy.
  9. Combining drugs that bypass p53 to treat TP53-mutated leukemias.
  10. E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis.
  11. UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.
  12. Megakaryocytes assemble a three-dimensional cage of extracellular matrix that controls their maturation and anchoring to the vascular niche.
  13. The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia.
  14. Digital twin models for predicting venetoclax and azacitidine-induced neutropenia in patients with acute myeloid leukemia.
  15. Immunophenotypic changes in the tumor and tumor microenvironment during progression to multiple myeloma.
  16. Automated classification of cellular expression in multiplexed imaging data with Nimbus.
  1. Blood. 2025 Oct 07. pii: blood.2024026505. [Epub ahead of print]
    A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.
    Francesca Matteini, Roshana Thambyrajah, Sara Montserrat-Vazquez, Sascha Jung, Alba Ferrer-Perez, Patricia Herrero Molinero, Dina El Jaramany, Javier Lozano-Bartolomé, Eva Mejia-Ramirez, Jessica Gonzalez Miranda, Antonio Del Sol, Anna Bigas, Maria Carolina Florian.
      Aged hematopoietic stem cells (HSCs) expand in clusters over time, while reducing their regenerative capacity and their ability to preserve the homeostasis of the hematopoietic system. The expression of Notch ligands in the bone marrow (BM) niche is essential for hematopoiesis. However, the impact of Notch signaling for adult HSC function and its involvement in HSC aging remains controversial. Here we show that Notch activation in young HSCs is not homogeneous, and it is triggered by sinusoidal expression of the Notch ligand Jagged2 (Jag2). Sinusoidal Jag2 deletion in young mice recapitulates the decrease in Notch activity observed in aged HSCs and alters HSC divisional symmetry and fate priming, promoting myeloid-biased HSCs (My-HSCs) expansion. Mechanistically, our data reveals that upon decreasing sinusoidal Jag2 expression, HSCs themselves upregulate Jag2, which cis-inhibits Notch signaling, resulting in the expansion of My-HSCs and in reduced hematopoietic regeneration. Collectively, these findings identify the crosstalk between BM niche-driven and HSC intrinsic features in regulating HSC fate priming and regenerative potential and reveal an extrinsic Notch trans-activation to intrinsic cis-inhibition switch underlying HSC aging.
    DOI:  https://doi.org/10.1182/blood.2024026505
  2. Blood. 2025 Oct 08. pii: blood.2025029513. [Epub ahead of print]
    Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche.
    James W Swann, Ruiyuan Zhang, Evgenia V Verovskaya, Fernando J Calero-Nieto, Xiaonan Wang, Melissa A Proven, Hiroyuki Hirakawa, Brian P Heubel, Peter T Shyu, X Edward Guo, Lei Ding, Berthold Gottgens, Emmanuelle Passegue.
      Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to complex conditions like inflammation remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations and accurately surveys both niche locations. We demonstrate that inflammatory perturbations exert specific effects on different cellular compartments, with type I interferon responses causing leptin receptor-expressing mesenchymal stromal cells to abandon their normal stromal functions and instead adopt an inflammatory phenotype associated with overproduction of chemokines that modulate local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.
    DOI:  https://doi.org/10.1182/blood.2025029513
  3. Ann Hematol. 2025 Oct 07.
    Microvesicles secreted by CoCl2-primed mesenchymal stromal cells boost the functionality of hematopoietic stem cells cultured with them.
    Shalmali Pendse, Vaijayanti Kale, Anuradha Vaidya.
      Rapid hematopoietic regeneration post-hematopoietic stem cell transplantation (HSCT) is vital for prompt immune recovery, infection prevention, and averting complications such as anemia and thrombocytopenia. The hematopoietic stem cells (HSCs) produce mature blood cells through a process known as hematopoiesis that is tightly regulated by the hypoxic bone marrow microenvironment. However, the limited number of HSCs present in the bone marrow is one of the major challenges for successful HSCT. Hence, developing novel ex vivo expansion strategies that address the clinical limitations of the current HSCT becomes imperative. Our prior work demonstrated that priming of mesenchymal stromal cells (MSCs) with a hypoxia-mimetic compound, cobalt chloride (CoCl2; CoCl2-MSCs) promotes the expansion of functional HSCs co-cultured with them. In this study, we investigated the role of CoCl2-MSCs-derived microvesicles (Co-MVs) and exosomes (Co-Exo) in regulating hematopoietic stem and progenitor cells (HSPCs). MVs and exosomes from naïve and atmospheric hypoxia (1% O2)-primed MSCs were used as controls. We found that CoCl2 induces the expression of Jagged-1-specific mRNA in the MSCs, which gets selectively partitioned into the Co-MVs. These Co-MVs, in turn, upregulate the expression of Notch2 and Hes1 in the HSPCs cultured with them. Furthermore, Co-MVs induce the expression of quiescence and self-renewal genes in the HSPCs and boost their long-term engraftment ability. These beneficial effects of Co-MVs on the functionality of HSPCs hold significant clinical implications as cell-free and cost-effective therapeutics in improving the success rate of HSCT.
    Keywords:  Extracellular vesicles; Hematopoietic stem and progenitor cells; Hypoxia; Mesenchymal stromal cells; Notch signaling pathway; Priming
    DOI:  https://doi.org/10.1007/s00277-025-06652-z
  4. Blood. 2025 Oct 08. pii: blood.2025028914. [Epub ahead of print]
    MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia.
    Dorien Pastoors, Marije Havermans, Roger Mulet-Lazaro, Leonie Smeenk, Sophie Ottema, Claudia A J Erpelinck-Verschueren, Stanley van Herk, Maikel Anthonissen, Tim Grob, Shruthi Subramanian, Julie A I Thoms, John E Pimanda, Bas J Wouters, Berna H Beverloo, Torsten Haferlach, Claudia Haferlach, Johannes Zuber, Eric Bindels, Ruud Delwel.
      The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells (HSCs) in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, encoding a transcription factor required for neutrophil development which is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42kb CEBPA enhancer. This is partially dependent on the interaction between MECOM and its co-repressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, AML patients with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects two major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
    DOI:  https://doi.org/10.1182/blood.2025028914
  5. Haematologica. 2025 Oct 09.
    Lineage bias in hematopoietic stem cells: more niche or intrinsic factors?
    Taha Bartu Hayal, Chuanfeng Wu.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.288704
  6. Blood Adv. 2025 Oct 07. pii: bloodadvances.2025017296. [Epub ahead of print]
    Ablation of CD38 in Multiple Myeloma Cells Leads to an Aggressive Phenotype in a Mouse Xenograft Model.
    Michael Riley Dyer, Alexander Zheleznyak, Erin N Teubner, Julie Prior, Brad Manion, Zhenghan Jing, Amit K Sharma, Junwei Du, Rui Tang, Mark A Fiala, John F DiPersio, Deborah Veis, Julie O'Neal, Mikhail Y Berezin, Monica Shokeen.
      Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and organ failure. A major challenge in treating MM is therapeutic resistance. CD38-targeted immunotherapies, such as daratumumab, have significantly improved outcomes, however, variable responses, resistance, and relapse remain challenges. We hypothesized that loss of CD38 drives a more aggressive phenotype and resistance to therapy. To test this, we developed a CD38 knockout (KO) clone of a human MM cell line and evaluated it in immunodeficient mice. Mice with CD38 KO tumors exhibited an increased tumor burden and reduced survival compared to those with CD38 WT tumors. Imaging and histology revealed increased osteolytic lesions caused by CD38 KO tumors, while FDG PET demonstrated elevated metabolic activity and tracer uptake in KO tumors. Mice with CD38 KO tumors also developed bilateral kidney metastases, whereas none occurred in WT tumors. Blood analysis showed elevated markers of disease progression and renal dysfunction, and cytokine profiling identified increased pro-inflammatory cytokines within the bone microenvironment. RNA-seq identified marked transcriptional changes, with enrichment of pathways involving cell adhesion, cytokine signaling, and migration. Daratumumab-resistant MM.1S cells mirrored CD38 KO cells with reduced cell cycle progression and dexamethasone sensitivity, underscoring the microenvironment's role in driving aggressiveness and implicating CD38 loss as a possible mediator of cross-resistance. Overall, these findings demonstrate that CD38 loss drives an aggressive MM phenotype characterized by bone degradation, renal metastasis, and reduced survival, highlighting the need to develop strategies to target CD38-deficient clones and offering RNA signatures as candidate regulators of this phenotype.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017296
  7. Adv Biol Regul. 2025 Sep 26. pii: S2212-4926(25)00046-6. [Epub ahead of print] 101119
    Induced pluripotent stem cell-based modelling of disease evolution in myeloid leukemia: MDS to AML.
    Jacqueline Boultwood.
      The myelodysplastic syndromes (MDS) are common myeloid malignancies that develop from the successive acquisition of driver mutations in hematopoietic stem cells residing in the bone marrow. Around a third of MDS patients will develop secondary acute myeloid leukemia (sAML) and patients with high-risk MDS or sAML have a dismal prognosis. The study of disease progression in myeloid malignancy has been enhanced in recent years by the use of induced pluripotent stem cells (iPSCs) technology. iPSCs offer the advantage of indefinite expansion and the potential for genetic modification, with reprogramming enabling the capture of the full complement of genetic lesions found in primary patient bone marrow samples. The power of iPSC and CRISPR-Cas9 gene editing technologies have been harnessed to generate a range of iPSC-based cellular models of MDS, reflecting the genetic and biologic heterogeneity of the disease. Stage-specific patient iPSC lines have been produced and sequential gene editing in normal human iPSCs has been performed to map the evolution of MDS to AML. These studies have increased our understanding of the impact of driver mutations, and co-mutations, on disease phenotype and revealed mechanisms underlying disease stage transitions in myeloid malignancy. iPSC-based models of MDS have also proven important tools in high throughput drug screening and have empowered drug testing and drug discovery, offering a new platform to develop personalized therapy.
    Keywords:  Acute myeloid leukemia; Disease evolution; Drug testing; Gene mutations; Induced pluripotent stem cells; Myelodysplastic syndromes
    DOI:  https://doi.org/10.1016/j.jbior.2025.101119
  8. Nat Biomed Eng. 2025 Oct 07.
    Large-scale generation of iNK and CAR-iNK cells from CD34+ haematopoietic stem and progenitor cells for adoptive immunotherapy.
    Fangxiao Hu, Jianhuan Li, Yao Wang, Yunqing Lin, Jingliao Zhang, Jiacheng Xu, Xiujuan Zheng, Qitong Weng, Xiaofei Liu, Yang Geng, Hongling Wu, Lijuan Liu, Huan Peng, Bingyan Wu, Dehao Huang, Chengxiang Xia, Tongjie Wang, Xin Du, Hui Zeng, Fang Dong, Yingchi Zhang, Xiaofan Zhu, Mengyun Zhang, Jinyong Wang.
      Chimaeric antigen receptor (CAR) natural killer (CAR-NK) cells are a promising alternative to CAR-T cells for immunotherapies. High and multiple doses of CAR-NK cell infusions are essential to maintain therapeutic efficacy in clinical trials, requiring efficient methods for generating CAR-NK cells at scale. Here we develop a three-step strategy to generate high yields of induced NK (iNK) and CAR-iNK cells from human umbilical cord blood CD34+ haematopoietic stem and progenitor cells (CD34+ HSPCs). Starting from a single umbilical cord blood unit of CD34+ HSPCs, our method produces 14-83 million mature iNK cells or 7-32 million CAR-iNK cells with high expression levels of CD16 and CAR and undetectable T-cell contamination. Both fresh and thawed iNK and CAR-iNK cells demonstrate anti-tumour activities against various human cancer cells and prolong the survival of human tumour-bearing animals. The high yields of CAR-NK cells and reduced costs of our method's CAR engineering support the broad applications of these cells for treating cancer patients.
    DOI:  https://doi.org/10.1038/s41551-025-01522-5
  9. Blood Adv. 2025 Oct 08. pii: bloodadvances.2025016683. [Epub ahead of print]
    Combining drugs that bypass p53 to treat TP53-mutated leukemias.
    Sudipta Biswas, Zeinab Zahran, Xiaorong Gu, Lisa Cardone, Remuna Marti, Nour Mouannes, Maximillian Stich, Akriti G Jain, Kateryna Fedorov, Benjamin K Tomlinson, Mendel Goldfinger, Amit Verma, Yogen Saunthararajah.
      Acute myeloid leukemias (AMLs) containing TP53 (p53) mutations are routinely treated with decitabine or 5-azacytidine which deplete DNA methyltransferase 1 (DNMT1)('hypomethylating agents', HMA). Unfortunately, resistance/relapse, characterized by preserved DNMT1, is rapid. HMA are pyrimidine analogs, and to deplete DNMT1, must compete with endogenous pyrimidines. These were substantially increased in HMA-resistant versus parental AML cells, together with upregulation of carbamoyl-phosphate-synthetase-2/aspartate transcarbamylase/dihydroorotase (CAD) that rate-limits de novo pyrimidine synthesis. Moreover, TP53-mutated AMLs appeared primed for such resistance with baseline higher CAD. Pyrimidine synthesis can be depowered by using the BCL2-inhibitor venetoclax to release BAX to depolarize mitochondrial membranes. However, BAX, a p53-target gene, was ~2-fold less expressed in TP53-mutated vs TP53-wildtype cells, and venetoclax impacts were correspondingly limited. Alternatively, pyrimidine synthesis can be inhibited directly at dihydroorotate dehydrogenase (DHODH) using the clinical drug teriflunomide. Contrasting with venetoclax, teriflunomide decreased pyrimidines several-fold, restored DNMT1-depletion, and cytoreduced HMA-resistant TP53-mutated AML cells via p53/apoptosis-independent terminal lineage-maturation. This non-cytotoxic pathway preserved viability and proliferation of normal hematopoietic stem/progenitor cells (HSPC). Inhibiting pyrimidine synthesis triggered automatic increases in pyrimidine salvage, such that schedules for teriflunomide combination with HMA, taken-up by salvage, mattered: in mice with TP53-mutated AML, teriflunomide scheduled day-before HMA was more efficacious than same-day or day-after. Chronic teriflunomide exposure paradoxically increased pyrimidines via sustained compensatory pyrimidine salvage, conferring resistance rather than sensitivity to HMA. In sum, DNMT1- and DHODH-targeting, administered by timed-intermittent (metronomic) schedules, can circumvent genetic-resistance caused by TP53-mutations, and adaptive-resistance caused by metabolic homeostasis, without cytotoxicity to normal HSPC.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016683
  10. Cell Death Dis. 2025 Oct 07. 16(1): 716
    E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis.
    Fei Xu, Chensheng Tan, Kun Tang, Guodong Qiao, Yu Shao, Xiaoping Li, Ji Zhou, Peijie Zhu, Mengyun Wu, Jiamin Cai, Xiu Gao, Yufeng Wang, Beibei Huang, Wenjun Wang, Tian Xia, Xuena Xu, Jiaoyang Li, Zhengrong Chen, Yufang Shi, Chuangli Hao, Yi Yang, Jinping Zhang.
      The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in macrophages remains unclear. Here, we identify both Cbl-b and c-Cbl (Cbls) as inhibitors of macrophage proliferation and promoters of macrophage apoptosis. Mechanically, we identify that Cbls functions upstream of AKT and Erk to mediate the ubiquitination and degradation of M-CSFR. M-CSF stimulation promotes dimerization and autophosphorylation activation of M-CSFR on the macrophage membrane, thereby activating downstream PI3K-AKT and Erk signaling pathways, leading to different biological effects such as macrophage proliferation and survival. At the same time, the Y559 site of the M-CSFR undergoes autophosphorylation, which can promote receptor recruitment and phosphorylation of Cbls. This promotes Cbls to induce K63-linked polyubiquitination at the K791 site of M-CSFR, leading to internalization and degradation of M-CSFR through lysosomal pathways, preventing excessive activation of the signaling pathway. Furthermore, Cbls deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and in vivo and dKO mice spontaneously develop a macrophage-dominated pulmonary enlargement. Together, these data demonstrate that Cbls play critical roles in the regulation of macrophage homeostasis by inhibiting M-CSFR-mediated AKT and Erk activation.
    DOI:  https://doi.org/10.1038/s41419-025-08047-4
  11. Nat Commun. 2025 Oct 09. 16(1): 8973
    UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.
    Aikaterini Vrentzou, Florian Leidner, Claudia C Schmidt, Helmut Grubmüller, Alexander Stein.
      Protein-lipid crosstalk is fundamental to homeostasis in the endoplasmic reticulum (ER). The ER-associated degradation (ERAD) pathway, a branch of the ubiquitin-proteasome system, maintains ER membrane properties by degrading lipid metabolic enzymes. However, the ERAD components that sense membrane properties and their mechanisms remain poorly defined. Using reconstituted systems with purified ERAD factors, we show that membrane composition modulates the ubiquitination cascade at multiple levels. The membrane-anchored E2 UBE2J2 acts as a sensor for lipid packing: in loosely packed membranes, UBE2J2 becomes inactive due to membrane association that impedes ubiquitin loading, while tighter packing promotes its active conformation and interaction with E1. UBE2J2 activity directs ubiquitin transfer by the E3 ligases RNF145, MARCHF6, and RNF139, targeting both themselves and the substrate squalene monooxygenase. Additionally, RNF145 senses cholesterol, altering its oligomerization and activity. These findings reveal that ERAD integrates multiple lipid signals, with UBE2J2 relaying and extending the effect of lipid signals through its cooperation with multiple E3 ligases.
    DOI:  https://doi.org/10.1038/s41467-025-64777-1
  12. Elife. 2025 Oct 08. pii: RP104963. [Epub ahead of print]14
    Megakaryocytes assemble a three-dimensional cage of extracellular matrix that controls their maturation and anchoring to the vascular niche.
    Claire Masson, Cyril Scandola, Jean-Yves Rinckel, Fabienne Proamer, Emily Janus-Bell, Fareeha Batool, Naël Osmani, Jacky G Goetz, Léa Mallo, Nathalie Brouard, Catherine Leon, Alicia Bornert, Renaud Poincloux, Olivier Destaing, Alma Mansson, Hong Qian, Maxime Lehmann, Anita Eckly.
      Megakaryocytes, the progenitor cells of blood platelets, play a crucial role in hemostasis by residing in the bone marrow and ensuring continuous platelet production. Unlike other hematopoietic cells, megakaryocytes do not enter the blood circulation intact. They remain anchored within the bone marrow while extending cytoplasmic protrusions called proplatelets through the sinusoidal endothelial barrier. These proplatelets subsequently fragment into functional platelets. This unique process of intravasation facilitates efficient platelet production while maintaining the megakaryocyte cell body within the bone marrow niche, thus preventing potential thrombotic complications. How the extracellular matrix (ECM) influences the delicate balance between megakaryocyte retention and proplatelet extension remains largely unknown. Here, we investigate the spatial organization and functional role of ECM components in the megakaryocyte vascular niche of mice bone marrow. Our findings reveal that laminin and collagen IV form three-dimensional (3D) ECM cages encompassing megakaryocytes and anchor them to the sinusoidal basement membrane. Gene deletion shows the existence of laminin α4 in the ECM cage that is necessary to maintain megakaryocyte-sinusoid interactions. Notably, megakaryocytes actively contribute to the ECM cage assembly; β1/β3 integrin knockout weakens these structures, increasing intravasation and entire megakaryocyte entry into circulation. The retention of megakaryocytes by these 3D ECM cages depends on dynamic remodeling processes. Inhibition of ECM proteolysis results in denser cage formation, increasing the frequency of immature megakaryocytes with impaired demarcation membrane system (DMS) development. Thus, the ECM cage represents a novel concept of an active and dynamic 3D microenvironment that is continuously remodeled and essential for maintaining megakaryocyte perivascular positioning. This specific microarchitecture guides megakaryocyte maturation and intravasation, underscoring the critical role of ECM microarchitecture and dynamics in megakaryocyte function.
    Keywords:  bone marrow; cell biology; extracellular matrix; megakaryocyte; mouse
    DOI:  https://doi.org/10.7554/eLife.104963
  13. Nat Commun. 2025 Oct 08. 16(1): 8964
    The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia.
    Louise Ahlgren, Mattias Pilheden, Helena Sturesson, Guangchun Song, Michael P Walsh, Minjun Yang, Maud Maillard, Huanbin Zhao, Zhongshan Cheng, Varsha Singh, Anders Castor, Cornelis Jan Pronk, Hanne Vibeke Marquart, Birgitte Lausen, Pauline Schneider, Gisela Barbany, Katja Pokrovskaja Tamm, Jonas Abrahamsson, Olli Lohi, Linda Fogelstrand, Pablo Menendez, Rob Pieters, Jinghui Zhang, Karin Lindkvist-Petersson, Jun J Yang, Tanja A Gruber, Ronald W Stam, Jing Ma, Anna K Hagström-Andersson.
      To study the mechanisms of relapse in KMT2A-rearranged (KMT2A-r) acute lymphoblastic (ALL) and acute myeloid leukemia (AML), we performed whole-genome and exome sequencing of infants and children with relapsed ALL/AML (n = 36), and longitudinal deep-sequencing of 257 samples in 30 patients. Somatic alterations in drug-response genes, most commonly in TP53 and IKZF1 (64%), were highly enriched in early relapse ALL (79%, 9-36 months after diagnosis), but rare in very early relapse ALL (<9 months, 9%). A marked chemotherapy-exposure signature was detected for mutations in early relapse ALL but not in very early ALL or AML relapse, in line with different mechanisms of relapse. Longitudinal analyses could track residual leukemia cells, clonal drug responses, and the upcoming relapse. These results highlight that KMT2A-r ALL and AML evade therapy differently and provide insights into the mechanisms of relapse in this highly lethal form of pediatric acute leukemia.
    DOI:  https://doi.org/10.1038/s41467-025-64190-8
  14. NPJ Digit Med. 2025 Oct 06. 8(1): 596
    Digital twin models for predicting venetoclax and azacitidine-induced neutropenia in patients with acute myeloid leukemia.
    Yue Zhang, Jonathan Martinez, Bahar Tercan, Heikki Kuusanmäki, Frank Emmert-Streib, Jerome G Chandraseelan, Amer Farea, Olli Yli-Harja, Caroline A Heckman, David L Gibbs, Vesteinn Thorsson, Ilya Shmulevich, Mika Kontro, Guangrong Qin, Boris Aguilar.
      Therapeutic toxicity, which can be life-threatening, presents a major challenge in treating patients with acute myeloid leukemia (AML). Medical digital twins, which are virtual representations of patient disease, have the potential to forecast disease progression and simulate potential treatments. Using neutrophil counts and blast percentages, we developed mechanistic models to predict toxicity (neutropenia) in AML patients receiving combination venetoclax and azacitidine treatment. We identified a best-fitting model, though patient-specific accuracy was highly variable. To address this variability, we investigated subsets of patients based on their accordance with model assumptions, and were able to identify features predictive of model fit. In addition, we found that continuous updating over time improves model accuracy. The model evaluated in this study could be further validated in a larger clinical setting and may support a digital twin for decision making in forecasting therapeutic toxicity of venetoclax and azacitidine treatment.
    DOI:  https://doi.org/10.1038/s41746-025-01978-4
  15. PLoS Genet. 2025 Oct 07. 21(10): e1011848
    Immunophenotypic changes in the tumor and tumor microenvironment during progression to multiple myeloma.
    Isabelle Bergiers, Murat Cem Köse, Sheri Skerget, Milan Malfait, Nele Fourneau, Jenna-Claire Ellis, Greet Vanhoof, Tina Smets, Bie Verbist, Dries De Maeyer, Jeroen Van Houdt, Koen Van der Borght, Raluca Verona, Bradley Heidrich, William Kurth, Michel Delforge, Nathalie Meuleman, Jan Van Droogenbroeck, Philip Vlummens, Christoph J Heuck, Yves Beguin, Nizar Bahlis, Tineke Casneuf, Jo Caers.
      Investigation of the cellular and molecular mechanisms of disease progression from precursor plasma cell disorders to active disease increases our understanding of multiple myeloma (MM) pathogenesis and supports the development of novel therapeutic strategies. In this analysis, single-cell RNA sequencing, surface protein profiling, and B lymphocyte antigen receptor profiling of unsorted, whole bone marrow (BM) mononuclear cell samples was used to study molecular changes in tumor cells and the tumor microenvironment (TME). A cell atlas of the BM microenvironment was generated from 123 subjects including healthy volunteers and patients with monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM. These analyses revealed commonalities in molecular pathways, including MYC signaling, E2F targets and interferon alpha response, that were altered during disease progression. Evidence of early dysregulation of the immune system in MGUS and SMM, which increases and impacts many cell types as the disease progresses, was found. In parallel with disease progression, population shifts in CD8 + T cells, macrophages, and classical dendritic cells were observed, and the resulting differences in CD8 + T cells and macrophages were associated with poor overall survival outcomes. Potential ligand-receptor interactions that may play a role during the transition from precursor stages to MM were identified, along with potential biomarkers of disease progression, some of which may represent novel therapeutic targets. MIF, IL15, CD320, HGF and FAM3C were detected as potential regulators of the TME by plasma cells, while SERPINA1 and BAFF (TNFSF13B) were found to have the highest potential to contribute to the downstream changes observed between precursor stage and MM cells. These findings demonstrate that myeloma tumorigenesis is associated with dysregulation of molecular pathways driven by gradually occurring immunophenotypic changes in the tumor and TME. Trial registration: This project has been registered at EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with protocol number NOPRODMMY0001 and EudraCT Number 2018-004443-23 on 12 December 2018.
    DOI:  https://doi.org/10.1371/journal.pgen.1011848
  16. Nat Methods. 2025 Oct;22(10): 2161-2170
    Automated classification of cellular expression in multiplexed imaging data with Nimbus.
    Josef Lorenz Rumberger, Noah F Greenwald, Jolene S Ranek, Potchara Boonrat, Cameron Walker, Jannik Franzen, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Candace C Liu, Inna Averbukh, Hadeesha Piyadasa, Rami Vanguri, Iris Nederlof, Xuefei Julie Wang, David Van Valen, Marleen Kok, Sean C Bendall, Travis J Hollmann, Dagmar Kainmueller, Michael Angelo.
      Multiplexed imaging offers a powerful approach to characterize the spatial topography of tissues in both health and disease. To analyze such data, the specific combination of markers that are present in each cell must be enumerated to enable accurate phenotyping, a process that often relies on unsupervised clustering. We constructed the Pan-Multiplex (Pan-M) dataset containing 197 million distinct annotations of marker expression across 15 different cell types. We used Pan-M to create Nimbus, a deep learning model to predict marker positivity from multiplexed image data. Nimbus is a pretrained model that uses the underlying images to classify marker expression of individual cells as positive or negative across distinct cell types, from different tissues, acquired using different microscope platforms, without requiring any retraining. We demonstrate that Nimbus predictions capture the underlying staining patterns of the full diversity of markers present in Pan-M, and that Nimbus matches or exceeds the accuracy of previous approaches that must be retrained on each dataset. We then show how Nimbus predictions can be integrated with downstream clustering algorithms to robustly identify cell subtypes in image data. We have open-sourced Nimbus and Pan-M to enable community use at https://github.com/angelolab/Nimbus-Inference .
    DOI:  https://doi.org/10.1038/s41592-025-02826-9
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