bims-scepro 2025-03-02 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–03–02
twenty-six papers selected by
William Grey, University of York

Decoding functional hematopoietic progenitor cells in the adult human lung.
Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.
Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.
NO-immune privilege for hematopoietic stem cells.
cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pretransplant Conditioning.
A CEBPB/IL-1β/TNF-α Feedback Loop Drives Drug Resistance to Venetoclax and MDM2 Inhibitors in Monocytic Leukemia.
Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.
CD34+CD38- leukemia stem cells predict clinical outcomes in acute myeloid leukemia patients treated non-intensively with hypomethylating agents.
Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
Iron trapping in macrophages reshapes the homeostasis of the haematopoietic system.
The bone marrow NK cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy.
NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.
The lncRNA DUBR is regulated by CTCF and coordinates chromatin landscape and gene expression in hematopoietic cells.
Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis.
PROTAC-induced protein structural dynamics in targeted protein degradation.
STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.
TRIM44 facilitates aggressive behaviors in multiple myeloma through promoting ZEB1 deubiquitination.
Distinct outcomes from targeted perturbations of the multi-subunit SCFSkp2 E3 ubiquitin ligase in blocking Trp53/Rb1-null prostate tumorigenesis.
Effects of mesenchymal stem cells from different sources on the biological functions of multiple myeloma cells.
Multiple Myeloma Insights from Single-Cell Analysis: Clonal Evolution, the Microenvironment, Therapy Evasion, and Clinical Implications.
Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells.
Molecular mechanisms of CAND2 in regulating SCF ubiquitin ligases.
Mass-spectrometry-based proteomics: from single cells to clinical applications.
Non-invasive in vivo monitoring of PROTAC-mediated protein degradation using an environment-sensitive reporter.
Endosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.
Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.

Blood. 2025 Feb 27. pii: blood.2024027884. [Epub ahead of print]

Decoding functional hematopoietic progenitor cells in the adult human lung.

Catharina Conrad, Melia Magnen, Jessica Tsui, Harrison Jacob Wismer, Mohammad Naser, Urmila Venkataramani, Bushra Samad, Simon J Cleary, Longhui Qiu, Jennifer J Tian, Marco De Giovanni, Nicole Mende, Andrew D Leavitt, Emmanuelle Passegue, Elisa Laurenti, Alexis J Combes, Mark R Looney.

While the bone marrow is the main site of blood cell production in adults, rare pools of hematopoietic stem and progenitor cells have been found in extramedullary organs. In mice, we have previously shown that the lungs contain hematopoietic progenitor cells and is a site of platelet production. Here, in the adult human lung, we show that functional hematopoietic precursors reside in the extravascular spaces with a frequency similar to the bone marrow, and are capable of proliferation and engraftment in mice. The gene signature of pulmonary and medullary CD34+ hematopoietic progenitors indicates greater baseline activation of immune, megakaryocyte/platelet and erythroid-related pathways in lung progenitors. Spatial transcriptomics mapped blood progenitors in the lung to an alveolar interstitium niche with only a few cells identified in an intravascular location. In human blood samples collected for stem cell transplantation, CD34+ cells with a lung signature enriched the mobilized pool of hematopoietic stem cells. These results identify the lung as a pool for uniquely programmed blood stem and progenitor cells with the potential to support hematopoiesis in humans.

DOI: https://doi.org/10.1182/blood.2024027884
Nat Immunol. 2025 Feb 25.

Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.

Tomer Itkin, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B Kaufmann, Laura Garcia-Prat, Gregory T Booth, Fuqiang Geng, Ying Liu, Jesus M Gomez-Salinero, Jae-Hung Shieh, David Redmond, Jenny Z Xiang, Steven Z Josefowicz, Cole Trapnell, Eric M Pietras, Joel A Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E Dick, Stephanie Z Xie, Shahin Rafii.

Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.

DOI: https://doi.org/10.1038/s41590-025-02087-w
Exp Hematol. 2025 Feb 25. pii: S0301-472X(25)00038-4. [Epub ahead of print] 104747

Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.

Samantha M Holmes, Christopher J Wells, Christine Hall, Amy J M McNaughton, Michael J Rauh, Sheela A Abraham.

  The precancerous expansion of hematopoietic cells, termed clonal hematopoiesis (CH), has been correlated to disease development and all-cause mortality. Despite multiple observations that hematopoietic stem cell and progenitors (HSPCs) are significantly affected by both sex and age, there remain few studies quantifying male and female HSPC populations in wild-type and transgenic Tet2 models over time. Here we determine that male mice (with a hematopoietic deficiency of Tet2 and control) have more Lin-Sca-1+c-kit+ (LSK) cells, that include multi-potent progenitor cells (MPP; LSK CD48-CD150-) and long-term hematopoietic stem cells (LT-HSC; LSK CD48-CD150+) compared to females. LT-HSC, MPP and progenitor populations were observed to possess equal male/female ratios in mice at 6 weeks of age; however, the LSK compartment was found most susceptible to sex-based effects in transgenic mice between 6 weeks and 4 months. In contrast, all differentiated progenitor populations analysed in mice were observed to be unaffected by sex between 6 weeks to 4 months. This study provides a comprehensive analysis of bone-sourced HSPCs in Tet2-deficient mouse models and reveals important sex and age considerations that must be taken into account when choosing mice for transgenic studies in C57BL/6 mice.

Keywords:  C57BL/6 mice; Clonal hematopoiesis; Mouse Models; Sex differences; Tet2

DOI:  https://doi.org/10.1016/j.exphem.2025.104747
Cell Res. 2025 Feb 28.

NO-immune privilege for hematopoietic stem cells.

Agathe L Chédeville, Simón Méndez-Ferrer.

DOI: https://doi.org/10.1038/s41422-025-01087-7
Blood. 2025 Feb 26. pii: blood.2024024636. [Epub ahead of print]

cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pretransplant Conditioning.

Daisuke Araki, So Gun Hong, Nathaniel Seth Linde, Bryan Fisk, Neelam Redekar, Christi T Salisbury-Ruf, Allen Krouse, Theresa Engels, Justin Golomb, Pradeep K Dagur, Sumith R Panicker, Yogendra Kanthi, Diogo Magnani, Zhirui Wang, Andre Larochelle.

The thrombopoietin (TPO):cMPL signaling axis is a critical regulator of early hematopoiesis. However, the utility of cMPL as a standalone marker for identifying long-term repopulating hematopoietic stem cells (LT-HSCs) within the adult human CD34+ cell hematopoietic stem and progenitor cell (HSPC) population has not been validated. In this study, we established high cMPL surface expression as a defining feature of human LT-HSCs. Targeting the cMPL receptor facilitated the separation of human LT-HSCs from mature progenitors, a delineation not achievable with cKIT. Leveraging this finding, we explored the therapeutic potential of cMPL as a novel target for pre-transplant conditioning regimens. We developed a cMPL-targeting immunotoxin, demonstrating its ability to preferentially deplete host cMPLhigh LT-HSCs in murine xenograft models. Evaluation in rhesus macaques confirmed these findings and highlighted a favorable safety profile with rapid systemic clearance within 24 hours of administration. Proof-of-concept experiments validated the immunotoxin as a novel conditioning agent, enabling donor HSPC engraftment without the use of chemotherapy or irradiation. These findings advance our understanding of the molecular determinants of human hematopoiesis and underscore the potential of cMPL-targeting preparative regimens to improve therapeutic transplantation outcomes.

DOI: https://doi.org/10.1182/blood.2024024636
Blood. 2025 Feb 26. pii: blood.2024028239. [Epub ahead of print]

A CEBPB/IL-1β/TNF-α Feedback Loop Drives Drug Resistance to Venetoclax and MDM2 Inhibitors in Monocytic Leukemia.

Basil Allen, Daniel Bottomly, Thomas Köhnke, Anthony Wang, Hsin-Yun Lin, Kara Johnson, Isabel Kenna, Anastatia Streltsova, Emma Martin, Reid Chen, Lindsey Savoy, Nicola Long, Peter Ryabinin, Stephen E Kurtz, Christopher A Eide, Amy Carlos, Andy Kaempf, Tingting Liu, Cristina E Tognon, Robert Searles, Paul D Piehowski, Sara J C Gosline, Anupriya Agarwal, Bill H Chang, Michelle Barton, Brian J Druker, Shannon K McWeeney, Ravindra Majeti, Jeffrey W Tyner, Haijiao Zhang.

MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor idasanutlin, like venetoclax, is ineffective against monocytic leukemia (FAB M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promotes monocytic differentiation, suppresses CASP3 and CASP6, and upregulates MCL1, BCL2A1, and the IL-1/TNF-α/NF-κB pathway members, conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. Additionally, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-α, which promotes monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1β and TNF-α only increase CEBPB levels and protect M4/M5 cells from these drugs, but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-α/NF-κB pathway, independent of FAB subtype, indicating a drug induced compensatory protection mechanisms. A combination of venetoclax/ idasanutlin with inhibitors that block IL-1/TNF-α pathway, demonstrate synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop involving CEBPB, IL-1/TNF-α, and monocyte differentiation in M4/M5 leukemia, which promotes both intrinsic and extrinsic drug resistance, along with drug-induced protection against venetoclax and MDM2 inhibitors.

DOI: https://doi.org/10.1182/blood.2024028239
Cell Stem Cell. 2025 Feb 19. pii: S1934-5909(25)00012-8. [Epub ahead of print]

Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.

Indranil Singh, Daniel Fernandez-Perez, Pedro Sanchez Sanchez, Alejo E Rodriguez-Fraticelli.

  Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations. Using mouse models, we studied two leukemic mutations, Dnmt3a-R878H and Npm1c, and found that their effect was highly variable across different stem cell states. Specifically, a subset of differentiation-primed stem cells, which normally becomes outcompeted with time, expands with both mutations. Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.

Keywords:  Dnmt3a; Npm1; cancer initiation; cell barcoding; cell of origin; clonal hematopoiesis; lineage tracing; myeloid leukemia; myeloid malignancies; single-cell

DOI:  https://doi.org/10.1016/j.stem.2025.01.012
Leukemia. 2025 Feb 27.

CD34+CD38- leukemia stem cells predict clinical outcomes in acute myeloid leukemia patients treated non-intensively with hypomethylating agents.

Tom Reuvekamp, Lok Lam Ngai, Daphne den Hartog, Jannemieke Carbaat-Ham, Mona M H E Fayed, Willemijn J Scholten, Tim R Mocking, Dana A Chitu, Thomas Pabst, Saskia K Klein, Georg Stussi, Laimonas Griskevicius, Dimitri Breems, Danielle van Lammeren-Venema, Rinske Boersma, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Costa Bachas, Gerwin Huls, David C de Leeuw, Jacqueline Cloos.

DOI: https://doi.org/10.1038/s41375-025-02539-0
Cell Stem Cell. 2025 Feb 17. pii: S1934-5909(25)00013-X. [Epub ahead of print]

Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.

Zemin Song, Yali Cui, Lilan Xin, Ruijing Xiao, Jingjing Feng, Conghui Li, Zhinang Yin, Honghong Wang, Qiuzi Li, Mengxuan Wang, Baoyi Lin, Yiming Zhang, Ying Zhou, Li Huang, Yanli He, Xiaoqing Li, Xiaoyan Liu, Shangqin Liu, Fuling Zhou, Zheng Liu, Hai-Bing Zhou, Pingping Fang, Kaiwei Liang.

  Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.

Keywords:  CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle

DOI:  https://doi.org/10.1016/j.stem.2025.01.013
Br J Haematol. 2025 Feb 26.

Iron trapping in macrophages reshapes the homeostasis of the haematopoietic system.

Laura Crisafulli, Margherita Correnti, Elena Gammella, Elisa De Camilli, Matteo Brindisi, Eleonora Palagano, Chiara Milanesi, Gabriele Todisco, Matteo G Della Porta, Cristina Sobacchi, Gaetano Cairo, Francesca Ficara, Stefania Recalcati.

  Iron is required for key physiological processes, like oxygen transport, energy production and cell proliferation. Body iron homeostasis is regulated by the erythroferrone-hepcidin-ferroportin (FPN) axis, which mainly acts on absorptive duodenal cells and macrophages involved in iron recycling from red blood cell breakdown. In addition to systemic iron regulation, macrophages are also involved in local iron release to neighbouring cells. Similarly, bone marrow (BM)-resident macrophages could represent promptly available local sources of iron for developing haematopoietic cells. To study the impact of macrophage-released iron on BM haematopoietic stem and progenitor cells, we employed mice with targeted deletion of Fpn in the myeloid lineage (Fpn conditional knockout or Fpn-cKO). Fpn-cKO mice develop age-related anaemia and microcytaemia, reduction of BM erythroblasts and preferential megakaryopoiesis at the expenses of erythropoiesis, suggesting that red cells are mostly affected by the lack of myeloid-derived iron delivery. Transferrin receptor 1 surface expression is higher in Fpn-cKO mice than littermate controls in all the BM subpopulation analysed, starting from haematopoietic stem cells, indicating a broad BM sensitivity to lower iron availability. Last, Fpn-cKO mice activate systemic compensatory mechanisms, such as extramedullary haematopoiesis and erythroferrone upregulation, albeit not sufficient to overcome anaemia.

Keywords:  anaemia; animal model; haematopoiesis; iron; macrophages; red cells

DOI:  https://doi.org/10.1111/bjh.20031
Blood. 2025 Feb 28. pii: blood.2024026455. [Epub ahead of print]

The bone marrow NK cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy.

Charlotte L B M Korst, Sabrin Tahri, Carolien Duetz, Wassilis S C Bruins, A Vera de Jonge, Madelon M E de Jong, Cathelijne Fokkema, Febe Smits, Kaz Groen, Christie P M Verkleij, Kristine A Frerichs, Natalie Papazian, Mark van Duin, Gregory van Beek, Remco Hoogenboezem, Thomas Baardemans, Giada Dal Collo, Elodie C G Stoetman, Meliha Cosovic, Inoka Twickler, Rosa Rentenaar, Merve Eken, Paola M Homan-Weert, Elona Saraci, Mattia D'Agostino, Vincent H J van der Velden, Mathijs Arnoud Sanders, Francesca Gay, Annemiek Broijl, Philippe Moreau, Pieter Sonneveld, Sonja Zweegman, Tuna Mutis, Tom Cupedo, Niels W C J van de Donk.

Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry and functional assays to investigate the bone marrow NK cell compartment of MM patients at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving MRD-negativity post-consolidation in patients treated with daratumumab, bortezomib, thalidomide and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial. In contrast, NK cell distribution did not predict MRD-negativity in patients treated in the control arm without daratumumab. These findings highlight the impact of the bone marrow NK cell compartment on therapeutic outcomes in MM patients receiving immunotherapy with CD38-targeting antibodies.

DOI: https://doi.org/10.1182/blood.2024026455
Blood. 2025 Feb 26. pii: blood.2024027020. [Epub ahead of print]

NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.

Francesco Tamiro, Costanzo Padovano, Elisabetta De Santis, Serena Di Iasio, Francesca Delia Sansico, Valentina Canistro, Mattia Colucci, Chiara Di Nunzio, Gaja Bruno, Kashish Doshi, Angela Totaro, Eric Gu, Michele Santodirocco, Andrew P Weng, Vincenzo Giambra.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by an expansion of T-cell progenitors and DNA mutations that lead to an overactive NOTCH1 signaling in over 50% of T-ALL cases. Using synthetic models of human T-ALL, we report that NOTCH1 dimeric signaling was crucial for the leukemogenesis of human hematopoietic stem/progenitor cells (HSPCs) from cord blood. We also identified a Notch-dimerization-dependent gene signature, including HES4 transcription factor, which induced proliferative advantage in human HSPCs as well as in Notch-dimerization-dependent patient-derived xenografts (PDXs) of T-ALL. Interestingly, in human T-ALL cells, HES4 enforced the expression of D133p53 isoform with the concomitant block of pro-apoptotic p53 target genes and the induction of BCL2L1 gene expression and anti-apoptotic Bcl-xL protein. Additionally, through an integrated experimental approach including genetically modified cell lines, RNA/Chip-sequencing and single cell RNA-sequencing (scRNA-Seq) profiles of primary T-ALL samples, we revealed cell subsets with Notch-dimerization-dependent gene signature, which indirectly correlated with pro-apoptotic genes as well as directly associated with cell markers of poor clinical outcome in primary T-ALL samples. Taken together, these findings highlight the crucial role of NOTCH1 dimeric signaling in human T-cell leukemogenesis and T-ALL maintenance suggesting that a possible benefit can be obtained from a therapeutic strategy targeting NOTCH1-dimer signaling or its downstream effectors.

DOI: https://doi.org/10.1182/blood.2024027020
Nucleic Acids Res. 2025 Feb 08. pii: gkaf093. [Epub ahead of print]53(4):

The lncRNA DUBR is regulated by CTCF and coordinates chromatin landscape and gene expression in hematopoietic cells.

Hober Nelson Núñez-Martínez, Gustavo Tapia-Urzúa, Ángel Josué Cerecedo-Castillo, Carlos Alberto Peralta-Alvarez, Georgina Guerrero, Maite Huarte, Félix Recillas-Targa.

Master hematopoietic transcription factors (TFs) and long noncoding RNAs (lncRNAs) coordinate shaping lineage-specific gene expression programs during hematopoietic differentiation. The architectural protein CCCTC-binding factor (CTCF) has emerged as a pivotal regulator of gene expression in cell differentiation. However, the relationship and its regulatory effect of CTCF on lncRNA genes in hematopoiesis remain elusive. We demonstrated that CTCF constrains the lncRNA DUBRtranscription throughout erythroid differentiation. DUBR is highly expressed in human hematopoietic stem and progenitor cells (HSPCs) but depleted in erythroblasts. DUBR perturbation dysregulates hematopoietic-erythroid cell differentiation genes and facilitates genome-wide activation of regulatory elements. A genomic map of RNA occupancy revealed that DUBR associates with a set of genes involved in regulating hematopoietic differentiation, including the erythroid repressor HES1, which targets a subset of regulatory elements of DUBR-dysregulated genes. Our results support the role of DUBR as a regulator of a hematopoietic differentiation gene program by coordinating the expression of genes and influencing their chromatin regulatory landscape.

DOI: https://doi.org/10.1093/nar/gkaf093
bioRxiv. 2025 Feb 12. pii: 2025.02.10.637540. [Epub ahead of print]

Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis.

Fang Zhou, Biljana Culjkovic-Kraljacic, Christian Bach, Li Feng, Yuta Mishima, Katherine L B Borden, Daniel G Tenen.

HoxA9, a homeodomain-containing transcription factor, is mis-expressed in over half of acute myeloid leukemia (AML) cases, and is associated with poor prognosis. Previous studies indicated that HoxA9 binds to the eukaryotic translation initiation factor eIF4E in primary specimens and that HoxA9 stimulated the RNA export and translation efficiency of selected RNAs via eIF4E. However, the relevance of this to its leukemogenic transformation capacity was unknown. Here, we used a double point mutation (HoxA9AA) to disrupt the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. Surprisingly, the mutation dramatically increased AML latency from a median of 90 to 280 days and resulted in incomplete penetrance. Re-transplantation of bone marrow cells from leukemic animals demonstrated even more pronounced differences in disease kinetics and penetrance with all animals succumbing to disease by day 60 in the wildtype group, while some HoxA9AA mice never developed leukemia. Collectively, these findings uncover a novel, transcription-independent mechanism of HoxA9-driven leukemogenesis through eIF4E and positions eIF4E as a potential therapeutic target AML patients expressing high levels of HoxA9.
Key Points: A double point mutation in HoxA9 disrupted the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature.Eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis and is important for the maintenance of acute myeloid leukemia.

DOI: https://doi.org/10.1101/2025.02.10.637540
Elife. 2025 Feb 27. pii: RP101127. [Epub ahead of print]13

PROTAC-induced protein structural dynamics in targeted protein degradation.

Kingsley Y Wu, Ta I Hung, Chia-En A Chang.

  PROteolysis TArgeting Chimeras (PROTACs) are small molecules that induce target protein degradation via the ubiquitin-proteasome system. PROTACs recruit the target protein and E3 ligase; a critical first step is forming a ternary complex. However, while the formation of a ternary complex is crucial, it may not always guarantee successful protein degradation. The dynamics of the PROTAC-induced degradation complex play a key role in ubiquitination and subsequent degradation. In this study, we computationally modelled protein complex structures and dynamics associated with a series of PROTACs featuring different linkers to investigate why these PROTACs, all of which formed ternary complexes with Cereblon (CRBN) E3 ligase and the target protein bromodomain-containing protein 4 (BRD4BD1), exhibited varying degrees of degradation potency. We constructed the degradation machinery complexes with Culling-Ring Ligase 4A (CRL4A) E3 ligase scaffolds. Through atomistic molecular dynamics simulations, we illustrated how PROTAC-dependent protein dynamics facilitating the arrangement of surface lysine residues of BRD4BD1 into the catalytic pocket of E2/ubiquitin cascade for ubiquitination. Despite featuring identical warheads in this PROTAC series, the linkers were found to affect the residue-interaction networks, and thus governing the essential motions of the entire degradation machine for ubiquitination. These findings offer a structural dynamic perspective on ligand-induced protein degradation, providing insights to guide future PROTAC design endeavors.

Keywords:  conformational sampling; drug development; molecular biophysics; molecular mechanics; molecular modeling; none; structural biology; structural dynamic; targeted protein degradation

DOI:  https://doi.org/10.7554/eLife.101127
Blood. 2025 Feb 26. pii: blood.2024026934. [Epub ahead of print]

STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.

Andreas Linder, Daniel Nixdorf, Niklas Kuhl, Ignazio Piseddu, Teng Teng Xu, Anne Verena Holtermann, Gunnar Kuut, Rebekka Elena Endres, Nora Philipp, Veit L Bücklein, Johann de Graaff, Thomas Carell, Sebastian Kobold, Roman Kischel, Veit Hornung, Marion Subklewe.

T-cell recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising results, early clinical trials have failed to demonstrate durable responses. We investigated whether activation of the innate immune system through stimulator of interferon genes (STING) can enhance target-cell killing by a BsAb targeting CD33 (CD33 BiTE® molecule, AMG 330). Indeed, we show that cytotoxicity against AML mediated by AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic GMP-AMP (cGAMP), or diABZI. We used in vitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR-Cas9 knockout experiments to investigate the enhancing effect of a STING agonist on the cytotoxicity of AMG 330 against AML. Importantly, we validated our findings with primary AML cells, and in a xenograft AML model. Mechanistically, in addition to direct cytotoxic effects of STING activation on AML cells, activated T cells render AML cells more susceptible to STING activation through their effector cytokines interferon-gamma (IFNγ) and tumor necrosis factor (TNF), resulting in enhanced type I interferon production and induction of interferon-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP/diABZI in enhancing AMG 330-mediated lysis. We established a key role for IFNγ in AMG 330-mediated cytotoxicity against AML cells, and in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.

DOI: https://doi.org/10.1182/blood.2024026934
Discov Oncol. 2025 Feb 27. 16(1): 248

TRIM44 facilitates aggressive behaviors in multiple myeloma through promoting ZEB1 deubiquitination.

Hui Qi, Jing Wang, Lixia Cao.

   BACKGROUND: Tripartite motif-containing 44 (TRIM44) involves in various tumor development. This study investigated role of TRIM44 in multiple myeloma (MM).
MATERIALS AND METHODS: TRIM44 levels in bone marrow tissues and MM cell lines was detected by quantitative reverse transcription PCR (RT-qPCR). Cell viability, migration, and invasion of MM cells were evaluated under the interference of TRIM44 expression. The role of TRIM44 on regulating tumor growth in vivo was also investigated in subcutaneous tumor xenograft models. The protein interact between TRIM44 and Zinc Finger E-Box Binding Homeobox 1 (ZEB1) was also studied according IP followed by western blotting assay.
RESULTS: TRIM44 was all highly expressed in collected bone marrow tissues and MM cell lines. Cell viability, migration, and invasion of MM cells with low expression of TRIM44 was significantly inhibited. Over-expression of TRIM44 can down-regulate the ZEB1 ubiquitination to enhance the protein stability.
CONCLUSIONS: TRIM44 exerts as an oncogenic factor to induce the oncogenesis of MM by stabilizing ZEB1.

Keywords:  Deubiquitination; Multiple myeloma; TRIM44; ZEB1

DOI:  https://doi.org/10.1007/s12672-025-01933-5
Commun Biol. 2025 Feb 22. 8(1): 278

Distinct outcomes from targeted perturbations of the multi-subunit SCFSkp2 E3 ubiquitin ligase in blocking Trp53/Rb1-null prostate tumorigenesis.

Yingjiao Xue, Liang Zhu, Saumen Karan, Joseph D Locker, Craig Branch, Jinghang Zhang, Bang Hoang, Juan Pablo Maianti, Hongling Zhao, Edward L Schwartz.

Identifying effective therapies targeting multi-protein complexes that lack catalytic sites or cofactor pockets remains a long-standing challenge. The proto-oncogene, ubiquitin E3 ligase SCFSkp2, is one such target. SCFSkp2 promotes the proteasomal degradation of the cyclin-dependent kinase inhibitor p27, which controls cell cycle progression. Targeted knockout of Rb1/Trp53 causes metastatic prostate cancer in mice; additional knockout of Skp2 completely blocks tumorigenesis. We compared gene-edited mice that carried two different single amino acid changes in the SCFSkp2 complex, structurally predicted to inhibit the degradation of p27. Mutation of the SCFSkp2 accessory protein Cks1 (Cks1N45R) completely blocked Rb1/Trp53-driven prostate tumorigenesis, phenocopying Skp2 knockout, whereas a mutation directly stabilizing p27 (p27T187A) did not. This was consistent with structural models that predicted the binding of both p27 and p27T187A to the SCFSkp2/Cks1/Cdk2/CyclinA/p27 complex, and their subsequent ubiquitination and degradation, albeit at different rates. Two binding modes, which differ in their dependence on phosphorylated T187, are predicted by the model. Studies confirmed the role of p27 in mediating tumorigenesis in Rb1/Trp53 mutant tumors and revealed a mutually destabilizing Skp2 and p27 feedback loop. The integration of gene editing, drug-surrogate mutations, and mouse tumor models offers a blueprint for studying SCFSkp2 and other multi-subunit biomedical targets.

DOI: https://doi.org/10.1038/s42003-025-07662-3
Stem Cell Res Ther. 2025 Feb 25. 16(1): 89

Effects of mesenchymal stem cells from different sources on the biological functions of multiple myeloma cells.

Yanju Li, Yang Liu, Xu Yang, Bo Yang, Jinyang Cheng, Juan Chen, Xiaoshuang Yuan, Xiao Xu, Guangyang Liu, Zhixu He, Feiqing Wang.

   BACKGROUND: The therapeutic benefits of mesenchymal stromal cells (MSCs) are largely dependent on paracrine factors, but the supernatants of the different MSCs may have different effects on multiple myeloma (MM) cells. Therefore, this study compared supernatants of bone marrow-derived mesenchymal stromal cells (BM-MSCs) with umbilical cord wharton's jelly's mesenchymal stem cells (UC-WJ MSCs) in different states (non-senescent and replicative senescence) on the MM cells.
METHODS: We extracted human BM-MSCs and UC-WJ MSCs in vitro and used H2O2 to induce replicative senescence. Concentrated supernatants from MSCs and senescent MSCs (SMSCs) were added to MM cells. Cell proliferation, the cell cycle, apoptosis, cell migration, tumor stemness factor expression, and cytokine expression levels were analyzed. Transcription regulation of signaling pathways was discussed.
RESULTS: We successfully isolated and identified BM-MSCs, UC-WJ MSCs, and SMSCs. When concentrated supernatants from BM-MSCs, UC-WJ MSCs, senescent BM-MSCs (SBM-MSCs), senescent UCWJ MSCs (SUC-WJ MSCs) were used to treat MM cells, BMMSCs and SBM-MSCs supernatants promoted the proliferation of MM cells, with a more pronounced effect by SBM-MSCs. UC-WJ MSCs and SUC-WJ MSCs supernatants inhibited the viability and proliferation of MM cells. BM-MSCs and SBM-MSCs supernatants increased the proportion of MM cells in the S-phase, with the effect of SBM-MSCs being more evident. UC-WJ MSCs and SUC-WJ MSCs supernatants arrested MM cells in the G0/G1 phase. BM-MSCs and SBM-MSCs supernatants enhanced the migration and tumor stemness of MM cells, with SBMMSCs having a more dramatic effect. UC-WJ MSCs and SUC-WJ MSCs supernatants inhibited the migration and tumor stemness of MM cells, with UC-WJ MSCs having a more inhibitory effect. IL-6 and VEGFA expression correlated negatively with the survival of patients with MM according to online database analysis, in addition, we found that the expression of IL-6 and VEGFA was higher in MM patients through GEO database analysis. BM-MSCs and SBM-MSCs supernatants treatment increased the expression of IL-6 and VEGFA on MM cells, while UC-WJ MSCs and SUC-WJ MSCs supernatants inhibited their expression. Signal pathway validation showed that the biological function of MSCs in MM is closely related to the PI3K/AKT/NF-κB pathway.
CONCLUSION: The supernatants of BM-MSCs promote the proliferation of MM cells, On the contrary, the supernatants of UC-WJ MSCs inhibit MM cell proliferation. We observed that MSCs from different sources and different states have contrasting biological functions in MM cells. Furthermore, this research was provided to the optimal cancer gene therapy vector for MM was UC-WJ MSCs, even UC-WJ MSCs was in the state of senescence.

Keywords:  Biological functions; Mesenchymal stem cells; Multiple myeloma; PI3K/AKT/NF-κB; Senescence

DOI:  https://doi.org/10.1186/s13287-025-04222-8
Cancers (Basel). 2025 Feb 14. pii: 653. [Epub ahead of print]17(4):

Multiple Myeloma Insights from Single-Cell Analysis: Clonal Evolution, the Microenvironment, Therapy Evasion, and Clinical Implications.

Sihong Li, Jiahui Liu, Madeline Peyton, Olivia Lazaro, Sean D McCabe, Xiaoqing Huang, Yunlong Liu, Zanyu Shi, Zhiqi Zhang, Brian A Walker, Travis S Johnson.

  Multiple myeloma (MM) is a complex and heterogeneous hematologic malignancy characterized by clonal evolution, genetic instability, and interactions with a supportive tumor microenvironment. These factors contribute to treatment resistance, disease progression, and significant variability in clinical outcomes among patients. This review explores the mechanisms underlying MM progression, including the genetic and epigenetic changes that drive clonal evolution, the role of the bone marrow microenvironment in supporting tumor growth and immune evasion, and the impact of genomic instability. We highlight the critical insights gained from single-cell technologies, such as single-cell transcriptomics, genomics, and multiomics, which have enabled a detailed understanding of MM heterogeneity at the cellular level, facilitating the identification of rare cell populations and mechanisms of drug resistance. Despite the promise of advanced technologies, MM remains an incurable disease and challenges remain in their clinical application, including high costs, data complexity, and the need for standardized bioinformatics and ethical considerations. This review emphasizes the importance of continued research and collaboration to address these challenges, ultimately aiming to enhance personalized treatment strategies and improve patient outcomes in MM.

Keywords:  clonal evolution; multiple myeloma; myeloma; omics; personalized medicine; scRNA-seq; single cell; single-cell technologies; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17040653
NEJM Evid. 2025 Mar;4(3): EVIDoa2400252

Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells.

Kasiani C Myers, Stella M Davies, Carolyn Lutzko, Robin Wahle, David D Grier, Geraldine Aubert, Kevin Norris, Duncan M Baird, Minako Koga, Akihiro C Ko, Tomokazu Amano, Misa Amano, Hong Yu, Minoru S H Ko.

BACKGROUND: Extremely short telomeres in patients with dyskeratosis congenita and related telomere biology disorders (TBDs) lead to premature cellular senescence and bone marrow failure. Zinc finger and SCAN domain-containing 4 (ZSCAN4) elongates telomeres by recombination.
METHODS: We report a clinical study in which EXG34217, the term given for autologous CD34+ hematopoietic stem cells from patients with TBD exposed to a temperature-sensitive Sendai virus vector encoding human ZSCAN4 at 33°C for 24 hours, was infused into patients without preconditioning.
RESULTS: Four patients were enrolled; two experienced successful CD34+ mobilization during the second mobilization attempt and underwent apheresis and EXG34217 infusion, with follow-up of 5 and 24 months (both ongoing). We observed telomere elongation (1.06- to 1.34-fold) in CD34+ cells ex vivo. In one patient, the treatment was associated with a change in the mean absolute neutrophil count (ANC) from 1.78×103 to 3.18×103 cells/μl; the lymphocyte subpopulation telomere length changed from 3.6 to 6.7 kb (50th percentile for age). In the other patient, the treatment was associated with a change in the lowest ANC from 0.6×103/μl to 1.2×103/μl; this has occurred in 5 months without the patient receiving prior intermittent low-dose granulocyte-colony-stimulating factor injections. During mobilization, all patients experienced mild to moderate bone pain or pain after line replacement, and one patient had a blood infection associated with fever and hypoxemia. After EXG34217 infusion, no acute safety issues were noted; in one patient mild to moderate long-term cardiac and pulmonary adverse events were noted; these were similar to symptoms of the patient's underlying conditions.
CONCLUSIONS: Although definitive conclusions cannot be drawn from the two EXG34217-treated patients, these results warrant further investigation of CD34+ cells exposed to ZSCAN4 for treating TBDs. (Funded by Elixirgen Therapeutics; ClinicalTrials.gov number, NCT04211714.).

DOI: https://doi.org/10.1056/EVIDoa2400252
Nat Commun. 2025 Feb 26. 16(1): 1998

Molecular mechanisms of CAND2 in regulating SCF ubiquitin ligases.

Kankan Wang, Lihong Li, Sebastian Kenny, Dailin Gan, Justin M Reitsma, Yun Zhou, Chittaranjan Das, Xing Liu.

Protein degradation orchestrated by SKP1·CUL1·F-box protein (SCF) ubiquitin ligases is a fundamental process essential for cellular and organismal function. The dynamic assembly of SCFs, facilitated by CAND1, ensures timely ubiquitination of diverse SCF target proteins. As a homolog of CAND1, CAND2 alone has been implicated in various human diseases, yet its functional mechanisms remain elusive. Here, we investigate the role of CAND2 in human cells and its distinct mode of action compared to CAND1. Using an array of quantitative assays, we demonstrate that CAND2 promotes SCF-mediated protein degradation as an F-box protein exchange factor. While CAND2 binds CUL1 with structure and affinity comparable to CAND1, it exhibits lower efficiency in exchanging F-box proteins. Kinetic measurements reveal a significantly higher KM for CAND2-catalyzed SCF disassembly than CAND1, which explains the lower exchange efficiency of CAND2 and is likely due to conformations of the CAND2·SCF exchange intermediate complex being less favorable for F-box protein dissociation. Our study provides mechanistic insights into the biochemical and structural properties of CAND2, as well as its role in regulating cellular dynamics of SCFs, laying a foundation for understanding contributions of CAND2 to healthy and diseased human cells.

DOI: https://doi.org/10.1038/s41467-025-57065-5
Nature. 2025 Feb;638(8052): 901-911

Mass-spectrometry-based proteomics: from single cells to clinical applications.

Tiannan Guo, Judith A Steen, Matthias Mann.

Mass-spectrometry (MS)-based proteomics has evolved into a powerful tool for comprehensively analysing biological systems. Recent technological advances have markedly increased sensitivity, enabling single-cell proteomics and spatial profiling of tissues. Simultaneously, improvements in throughput and robustness are facilitating clinical applications. In this Review, we present the latest developments in proteomics technology, including novel sample-preparation methods, advanced instrumentation and innovative data-acquisition strategies. We explore how these advances drive progress in key areas such as protein-protein interactions, post-translational modifications and structural proteomics. Integrating artificial intelligence into the proteomics workflow accelerates data analysis and biological interpretation. We discuss the application of proteomics to single-cell analysis and spatial profiling, which can provide unprecedented insights into cellular heterogeneity and tissue architecture. Finally, we examine the transition of proteomics from basic research to clinical practice, including biomarker discovery in body fluids and the promise and challenges of implementing proteomics-based diagnostics. This Review provides a broad and high-level overview of the current state of proteomics and its potential to revolutionize our understanding of biology and transform medical practice.

DOI: https://doi.org/10.1038/s41586-025-08584-0
Nat Commun. 2025 Feb 22. 16(1): 1892

Non-invasive in vivo monitoring of PROTAC-mediated protein degradation using an environment-sensitive reporter.

Tao Li, Qingyu Zong, He Dong, Ihsan Ullah, Zhenhai Pan, Youyong Yuan.

Proteolysis targeting chimeras (PROTACs) represent a groundbreaking therapeutic technology for selectively degrading proteins of interest (POIs). The structural variations in PROTACs unpredictably influence their protein degradation efficiency, which is predominantly assessed by quantifying POIs abundance through western blotting. This approach, however, falls short of enabling non-invasive monitoring of protein degradation within living cells let alone assessing directly the degradation effects in vivo. Herein, we develop an environment-sensitive reporter (ESR) for the quantification of protein degradation events triggered by PROTACs in vivo. By simultaneously integrating POIs targeting ligand and an environment-sensitive fluorophore, the ESR signals exhibit a strong fluorescence correlation with the levels of POIs. This non-invasive monitoring reporter offers a high-throughput and convenient way to screen POIs targeting degraders and predict PROTACs-mediated therapeutic outcomes in mouse models. These properties suggest the potential of ESR strategy as a general modular scheme for non-invasive quantification of protein degradation of cancer-related therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-57191-0
Elife. 2025 Feb 24. pii: RP99373. [Epub ahead of print]13

Endosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.

Hyunggu Hahn, Carole Daly, John Little, Nicole A Perry-Hauser, Emmanuel Flores-Espinoza, Asuka Inoue, Bianca Plouffe, Alex R B Thomsen.

  Chemokine receptors are GPCRs that regulate the chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors contain features associated with the ability to stimulate G protein signaling during β-arrestin-mediated receptor internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays a major role in cell migration, we chose to investigate the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying a combination of pharmacological and cell biological approaches, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation, which enables internalized receptors to activate G protein from endosomes. Furthermore, spatiotemporal-resolved APEX2 proteome profiling shows that endosomal CCR7 uniquely enriches specific Rho GTPase regulators as compared to plasma membrane CCR7, which is directly associated with enhanced activity of the Rho GTPase Rac1 and chemotaxis of immune T cells. As Rac1 drives the formation of membrane protrusions during chemotaxis, our findings suggest an important integrated function of endosomal chemokine receptor signaling in cell migration.

Keywords:  CCR7; cell biology; chemokine receptor; chemotaxis; endosomal signaling; human; spatiotemporal-resolved proteomics

DOI:  https://doi.org/10.7554/eLife.99373
Blood. 2025 Feb 26. pii: blood.2024025643. [Epub ahead of print]

Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.

Matteo Claudio Da Viá, Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Claudio De Magistris, Loredana Pettine, Antonio Giovanni Solimando, Vanessa Desantis, Giuseppe M Peretti, Laura Mangiavini, Riccardo Giorgino, Sonia Fabris, Stefania Pioggia, Alfredo Marchetti, Marzia Barbieri, Silvia Lonati, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Emanuele Calvi, Nayyer Latifinavid, Giancarlo Castellano, Federica Torricelli, Antonino Neri, Cathelijne Fokkema, Tom Cupedo, Marta Lionetti, Francesco Passamonti, Niccolò Bolli.

Multiple Myeloma is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumorigenic microenvironment (TME). To investigate if residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNAseq and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Out of n=234,789 PCs, 64,432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance (MGUS) to 3.23% in MMs (p=0.00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (i.e. CD38, CD138), while others were more variable (CD27, ITGB7). Only cPCs overexpressed oncogenes (e.g. CCND1/2, NSD2), but CCND3 was often expressed in pPCs. BCMA was expressed on both p- and cPCs, while GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon related pathways where significantly enriched in pPCs from patients vs HDs (p-adjusted < 0.05) showing an inflamed phenotype affecting genotypically normal PCs. Function of pPCs was consequently impacted and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNAseq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass dataset and predicted significantly better PFS and OS (log rank p < 0.05 for both). Our findings show that genotypic, single-cell identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.

DOI: https://doi.org/10.1182/blood.2024025643