bims-scepro 2025-01-12 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–01–12
25 papers selected by
William Grey, University of York

How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.
IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.
Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases.
Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis.
IFN alpha signaling drives hematopoietic stem cells malfunction under acute inflammation.
Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages.
Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models.
Dual ASXL1 and CSF3R mutations drive myeloid biased stem cell expansion and enhance neutrophil differentiation.
Hormonally mediated mechanical remodelling of human haematopoietic stem cells enhances their bone-marrow engraftment.
Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.
High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection.
Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence.
Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice.
Survival of Human Bone Marrow Plasma Cells In Vitro Depends on the Support of the Stromal Cells, PI3K, and Canonical NF-kappaB Signaling.
Spatiotemporal dynamics of fetal liver hematopoietic niches.
Novel classification system and high-risk categories of pediatric acute myeloid leukemia.
MicroRNA Screening Reveals Upregulation of FoxO-Signaling in Relapsed Acute Myeloid Leukemia Patients.
Tunneling nanotubes between bone marrow stromal cells support transmitophagy and resistance to apoptosis in myeloma.
Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.
Chronic viral mimicry induction following p53 loss promotes immune evasion.
Topology-based segmentation of 3D confocal images of emerging hematopoietic stem cells in the zebrafish embryo.
Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma.
Human Pluripotent Stem Cell-Derived Hematopoietic Progenitors and Mature Cells.
PTMNavigator: interactive visualization of differentially regulated post-translational modifications in cellular signaling pathways.

Exp Hematol. 2025 Jan 07. pii: S0301-472X(25)00002-5. [Epub ahead of print] 104711

How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.

Xueling Li, Jianwei Wang, Linping Hu, Tao Cheng.

Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation towards myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the update understanding of age-related changes in HSPCs and the mechanisms underlie the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.

DOI: https://doi.org/10.1016/j.exphem.2025.104711
Nat Immunol. 2025 Jan 09.

IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.

Brendan M Barton, Francheska Son, Akanksha Verma, Saswat Kumar Bal, Qianzi Tang, Rui Wang, Katharine Umphred-Wilson, Rehan Khan, Josephine Trichka, Han Dong, Claudia Lentucci, Xi Chen, Yinghua Chen, Yuning Hong, Cihangir Duy, Olivier Elemento, Ari M Melnick, Jin Cao, Xi Chen, Laurie H Glimcher, Stanley Adoro.

Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt-β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an '18-gene signature' of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α-XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.

DOI: https://doi.org/10.1038/s41590-024-02063-w
Blood. 2024 Dec 27. pii: blood.2024025598. [Epub ahead of print]

Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases.

Apeksha Singh, Jennifer J Chia, Dinesh S Rao, Alexander Hoffmann.

Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) amongst hematopoietic stem and progenitor cells (HSPCs). While HSC differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which shows increased myeloid-biased MPPs. We interpreted these data with differential equations models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term (ST) HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation-trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification amongst HSCs, but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation-trajectories supported increased proliferation amongst these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice, as well as human myeloid neoplasm patients. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.

DOI: https://doi.org/10.1182/blood.2024025598
Leukemia. 2025 Jan 07.

Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis.

Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M Pruett-Miller, Shai Izraeli, Wilson K Clements, John D Crispino.

GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we describe a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2R396Q/+. While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that Gata2R396Q/+ exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced and altered pool of HSCs could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.

DOI: https://doi.org/10.1038/s41375-024-02508-z
Int Immunopharmacol. 2025 Jan 06. pii: S1567-5769(25)00001-3. [Epub ahead of print]147 114012

IFN alpha signaling drives hematopoietic stem cells malfunction under acute inflammation.

Xue Han, Minyi Zhao, Kexin Wang, Weiwei Ma, Binghuo Wu, Yueyang Yu, Xiaomei Liang, Wenjian Mo, Xiaowei Chen, Ming Zhou, Yumiao Li, Shilin Xu, Uet Yu, Yalan Yang, Peng Lei, Ruiqing Zhou, Shunqing Wang.

Inflammation stimulation regulates the activity of hematopoietic stem cells (HSCs) through direct-sensing and cytokine-mediation. It is known that HSCs directly sense lipopolysaccharide (LPS), a classical infection-related inflammatory signal, via toll like receptor 4 (TLR4) and subsequently become active. However, the mechanism underlying the activity change of HSCs induced by LPS remains incompletely disclosed. Here we explored that under LPS stimulation, the activation of interferon alpha (IFNα) signal pathway resulted in the activation and exhaustion of HSCs in vitro, indicating HSCs directly responded to LPS through the downstream IFNα signal pathway. We also discovered the increased production of IFNα in mice bone marrow and expression of interferon-α/β receptor (IFNAR) on mice HSCs after LPS stimulation. Creatine, an IFNα inhibitor, could reverse the activation and prevent the exhaustion of HSCs caused by LPS by suppressing the expressions of genes associated with the IFNα signal pathway both in vitro and in vivo. Furthermore, we found that the IFNAR deficiency in mice effectively protected HSCs from activation, elevated apoptosis and impaired reconstitution ability under LPS stimulation in vivo. This finding further supports the notion that LPS activates and injures HSCs indirectly via promoting IFNα secretion in the bone marrow environment. Overall, our findings reveal that LPS causes the injury to HSCs either through direct or cytokine-mediated indirect activation of the IFNα signal pathway.

DOI: https://doi.org/10.1016/j.intimp.2025.114012
J Clin Invest. 2025 Jan 09. pii: e184069. [Epub ahead of print]

Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.

Jue Li, Jie Bai, Vincent T Pham, Michihiro Hashimoto, Maiko Sezaki, Qili Shi, Qiushi Jin, Chenhui He, Amy Armstrong, Tian Li, Mingzhe Pan, Shujun Liu, Yu Luan, Hui Zeng, Paul R Andreassen, Gang Huang.

  Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a leads to HSC defects, including loss of HSC quiescence and self-renewal, and increased differentiation. Mechanistically, we find that loss of Cpt1a results in elevated levels of mitochondrial respiratory chain complex components and their activities, as well as increased ATP production, and accumulation of mitochondrial reactive oxygen species (mitoROS) in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate a novel role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.

Keywords:  Hematology; Hematopoietic stem cells; Metabolism

DOI:  https://doi.org/10.1172/JCI184069
Blood. 2025 Jan 07. pii: blood.2024025402. [Epub ahead of print]

Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages.

Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimua, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue.

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we employed tRNASec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

DOI: https://doi.org/10.1182/blood.2024025402
Haematologica. 2025 01 09.

Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models.

Anna MP Stanger, Marlon Arnone, Pauline Hanns, Lucca M Kimmich, Jessica Kübler, Sarah Gekeler, Elsa S Görsch, Lea Kramer, Marcelle Baer, Jan C Schroeder, Taylor S Mills, Martina Konantz, Saskia S Rudat, Claudia Lengerke.

In acute myeloid leukemia (AML), leukemogenesis depends on cell-intrinsic genetic aberrations and thus, studies on AML require investigations in an in vivo setting as provided by patient derived xenografts (PDX) models. Here we report that, next to leukemic cell characteristics, recipient sex highly influences the outgrowth of AML cells in PDX models, with females being much better repopulated than males in primary as well as secondary transplantation assays. Testosterone may be the more important player since, strikingly, better engraftment was seen in castrated versus control male recipients, while ovariectomy did not significantly impair engraftment in females. Shorter time-to-engraftment and mouse survival were observed with adverse molecular risk, and respectively with high FLT3-ITD ratio mutated AML cells. Adverse risk AML furthermore showed higher percentages of phenotypic leukemic stem cells (LSCs), suggesting impaired differentiation capacity in these AML subtypes. Overall, we achieved successful repopulation with 14/23 (61%) favorable, 18/30 (60%) intermediate and 4/8 (50%) adverse risk AML cases in female recipient PDX models. Our data identify recipient sex as an important experimental confounder in leukemia PDX models, and the contribution of the sex hormones to leukemogenesis as an intriguing, underexplored research area.

DOI: https://doi.org/10.3324/haematol.2023.284647
Blood Adv. 2025 Jan 07. pii: bloodadvances.2024014362. [Epub ahead of print]

Dual ASXL1 and CSF3R mutations drive myeloid biased stem cell expansion and enhance neutrophil differentiation.

Lucie Darmusey, Anna J Bagley, Thai T Nguyen, Hanqian L Carlson, Hunter Blaylock, Shawn B Shrestha, Amara Pang, Samantha Tauchmann, Sarah C Taylor, Amy C Foley, Katia E Niño, Eric M Pietras, Theodore P Braun, Julia E Maxson.

Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). CNL is a myeloproliferative neoplasm (MPN) driven by activating mutations in the Colony Stimulating Factor 3 Receptor (CSF3R), which cause excessive neutrophil production. Despite the high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human MPNs. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem cells, which is tempered by adding of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased long-term hematopoietic stem cells. As the mice age, they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation, activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations have increased H3K4me1 at neutrophil-associated enhancers. Mutant ASXL1 is known to decrease the genome-wide abundance of the repressive histone mark H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1 and CSF3R dual mutant MPN.

DOI: https://doi.org/10.1182/bloodadvances.2024014362
Nat Biomed Eng. 2025 Jan 07.

Hormonally mediated mechanical remodelling of human haematopoietic stem cells enhances their bone-marrow engraftment.

DOI: https://doi.org/10.1038/s41551-024-01310-7
Sci Transl Med. 2025 Jan 08. 17(780): eadn9832

Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.

Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R Calvo, Natalie T Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A Godley, Marshall S Horwitz, Sioban Keel, Lucio H Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal.

Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (n = 10) combined with functional analysis of samples from patients with RUNX1-FPD (n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1-FPD and prevent myeloid progression.

DOI: https://doi.org/10.1126/scitranslmed.adn9832
Nat Commun. 2025 Jan 07. 16(1): 446

High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection.

Daniel T Claiborne, Zachary Detwiler, Steffen S Docken, Todd D Borland, Deborah Cromer, Amanda Simkhovich, Youdiil Ophinni, Ken Okawa, Timothy Bateson, Tao Chen, Wesley Hudson, Radiana Trifonova, Miles P Davenport, Tony W Ho, Christian L Boutwell, Todd M Allen.

The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mortality of such allogeneic transplants precludes widespread adoption of this HIV cure. Here, we show the application of CRISPR/Cas9 to achieve >90% CCR5 editing in human, mobilized hematopoietic stem progenitor cells (HSPC), resulting in a transplant that undergoes normal hematopoiesis, produces CCR5 null T cells, and renders xenograft mice refractory to HIV infection. Titration studies transplanting decreasing frequencies of CCR5 edited HSPCs demonstrate that <90% CCR5 editing confers decreasing protective benefit that becomes negligible between 54% and 26%. Our study demonstrates the feasibility of using CRISPR/Cas9/RNP to produce an HSPC transplant with high frequency CCR5 editing that is refractory to HIV replication. These results raise the potential of using CRISPR/Cas9 to produce a curative autologous HSCT and bring us closer to the development of a cure for HIV infection.

DOI: https://doi.org/10.1038/s41467-025-55873-3
medRxiv. 2024 Dec 16. pii: 2024.12.13.24318504. [Epub ahead of print]

Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence.

Francesco Mazziotta, Lauren E Martin, Daniel N Eagan, Merav Bar, Sinéad Kinsella, Kelly G Paulson, Valentin Voillet, Miranda C Lahman, Daniel Hunter, Thomas M Schmitt, Natalie Duerkopp, Cecilia Yeung, Tzu-Hao Tang, Raphael Gottardo, Yuta Asano, Elise C Wilcox, Bo Lee, Tianzi Zhang, Paolo Lopedote, Livius Penter, Catherine J Wu, Filippo Milano, Philip D Greenberg, Aude G Chapuis.

Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+ T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (TTCR-C4). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCRC4-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting TTCR-C4 skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained TTCR-C4 effector-memory profile correlated with long-term TTCR-C4 persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.

DOI: https://doi.org/10.1101/2024.12.13.24318504
Blood. 2024 Dec 27. pii: blood.2024025406. [Epub ahead of print]

Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice.

Maria Katariina Kauppi, Craig D Hyland, Elizabeth M Viney, Christine Anne White, Carolyn A de Graaf, AnneMarie E Welch, Jumana Yousef, Laura F Dagley, Samantha J Emery-Corbin, Ladina Di Rago, Andrew J Kueh, Marco J Herold, Douglas J Hilton, Jeffrey J Babon, Nicos A Nicola, Kira Behrens, Warren S Alexander.

Cullin-5 (Cul5) coordinates assembly of cullin-RING-E3 ubiquitin (Ub) ligase (CRL) complexes that include Suppressor of Cytokine Signaling (SOCS)-box-containing proteins. The SOCS-box proteins function to recruit specific substrates to the complex for ubiquitination and degradation. In hematopoiesis, SOCS-box proteins are best known for regulating the actions of cytokines that utilize the JAK-STAT signaling pathway. However, the roles of most SOCS-box proteins have not been studied in physiological contexts and any actions for Cul5/SOCS complexes in signaling by several hematopoietic cytokines, including thrombopoietin (TPO) and interleukin-3 (IL-3), remain unknown. To define additional potential roles for Cul5/SOCS complexes, we generated mice lacking Cul5 in hematopoiesis; the absence of Cul5 is predicted to impair the SOCS-box-dependent actions of all proteins that contain this motif. Here, we show that Cul5-deficient mice develop excess megakaryopoiesis and thrombocytosis revealing a novel mechanism of negative regulation of megakaryocyte-committed stem cells, a distinct population within the hematopoietic stem cell pool that have been shown to rapidly, perhaps directly, generate megakaryocytes, and which are produced in excess in the absence of Cul5. Cul5-deficient megakaryopoiesis is distinctive in being largely independent of TPO/Mpl and involves signaling via the beta-common and/or beta-IL-3 receptors, with evidence of deregulated responses to IL-3. This process is independent of the interferon-alpha/beta receptor (IFNARI), previously implicated in inflammation-induced activation of stem-like megakaryocyte progenitor cells.

DOI: https://doi.org/10.1182/blood.2024025406
Eur J Immunol. 2025 Jan;55(1): e202451358

Survival of Human Bone Marrow Plasma Cells In Vitro Depends on the Support of the Stromal Cells, PI3K, and Canonical NF-kappaB Signaling.

Zehra Uyar-Aydin, Shirin Kadler, Roland Lauster, Sina Bartfeld, Mark Rosowski.

  Contrary to short-lived plasma cells, which survive only 3-5 days, long-lived plasma cells (LLPCs) contribute to the humoral memory of the body and thus also to many antibody-related diseases. The ability of plasma cells to persist over months, years, and even a lifetime has been demonstrated in vivo. Yet, the in vitro culture of human primary bone marrow-derived plasma cells has been limited to a few days. Here, we establish culture conditions for human primary bone marrow-derived plasma cells for 21 days. Plasma cells and stromal cells are isolated from human bone marrow and cultured in 2D or a 3D ceramic scaffold. The plasma cells' survival and antibody secretion depend on direct contact with stromal cells. The culture promotes CD19-negative PCs. Inhibition of the PI3K or NF-kappaB pathways using chemical inhibitors reduced the survival of the plasma cells. These results underline the supportive role of the stromal cells for the survival of the LLPC and confirm mechanisms that were identified in mouse LLPCs also for human LLPCs. The culture described here will promote further studies to deepen our understanding of the human LLPC.

Keywords:  bone marrow; human culture model; memory cells; plasma cell

DOI:  https://doi.org/10.1002/eji.202451358
J Exp Med. 2025 Feb 03. pii: e20240592. [Epub ahead of print]222(2):

Spatiotemporal dynamics of fetal liver hematopoietic niches.

Márcia Mesquita Peixoto, Francisca Soares-da-Silva, Valentin Bonnet, Yanping Zhou, Gustave Ronteix, Rita Faria Santos, Marie-Pierre Mailhe, Gonçalo Nogueira, Xing Feng, João Pedro Pereira, Emanuele Azzoni, Giorgio Anselmi, Marella F T R de Bruijn, Archibald Perkins, Charles N Baroud, Perpétua Pinto-do-Ó, Ana Cumano.

Embryonic hematopoietic cells develop in the fetal liver (FL), surrounded by diverse non-hematopoietic stromal cells. However, the spatial organization and cytokine production patterns of the stroma during FL development remain poorly understood. Here, we characterized and mapped the hematopoietic and stromal cell populations at early (E12.5-14.5) FL stages, revealing that while hepatoblasts were the primary source of hematopoietic growth factors, other stromal cells-including mesenchymal, mesothelial, and endothelial cells-also contributed to this signaling network. Using a dedicated image analysis pipeline, we quantified cell distances to tissue structures and defined neighbor relationships, uncovering that different hematopoietic progenitors exhibit distinct preferences for neighboring stromal cells and show developmental changes in spatial distribution. Notably, our data suggest that the sub-mesothelium region plays a prominent role in early fetal hematopoiesis. This approach offers a valuable tool for studying complex cellular interactions in biological systems, providing new insights into hematopoietic niche organization during development.

DOI: https://doi.org/10.1084/jem.20240592
Haematologica. 2025 Jan 09.

Novel classification system and high-risk categories of pediatric acute myeloid leukemia.

Masayuki Umeda, Yen-Chun Liu, Seth E Karol, Jeffery M Klco.

The prognosis of pediatric acute myeloid leukemia (AML) remains poor compared with pediatric acute lymphoblastic leukemia (ALL); accurate diagnosis and treatment strategies based on the genomic background are strongly needed. Recent advances in sequencing technologies have identified novel pediatric AML subtypes, including BCL11B structural variants and UBTF tandem duplications (UBTF-TD), associated with poor prognosis. In contrast, these novel subtypes do not fit into the diagnostic systems for AML of the 5th edition WHO classification or International Consensus Classifications (ICC) released in 2022. In this review, we describe the current state of pediatric AML classification in the context of a new classification framework based on the findings of updated genomic profiling. Molecular categories in the new classification system are associated with unique transcriptional, mutational, and clinical characteristics, which can be leveraged for predicting clinical outcomes and developing molecular-target therapies based on the initiating driver alterations. We also highlight four high-risk subtypes of pediatric AML, namely CBFA2T3::GLIS2, BCL11B, UBTF-TD, and ETS family fusions, focusing on their disease mechanisms, clinical associations, and possible therapeutic strategies to overcome the dismal clinical outcomes associated with these alterations.

DOI: https://doi.org/10.3324/haematol.2024.285644
Genes (Basel). 2024 Dec 19. pii: 1625. [Epub ahead of print]15(12):

MicroRNA Screening Reveals Upregulation of FoxO-Signaling in Relapsed Acute Myeloid Leukemia Patients.

Paula Reichelt, Stephan Bernhart, Uwe Platzbecker, Michael Cross.

  Background/Objectives: AML is an aggressive malignant disease characterized by aberrant proliferation and accumulation of immature blast cells in the patient's bone marrow. Chemotherapeutic treatment can effectively induce remission and re-establish functional hematopoiesis. However, many patients experience chemoresistance-associated relapse and disease progression with a poor prognosis. The identification of molecular determinants of chemoresistance that could serve as potential targets for the therapeutic restoration of chemosensitivity has proven to be challenging. Methods: To address this, we have analyzed longitudinal changes in the expression of microRNAs during disease progression in a small set of four AML patients, combined with gene ontology (GO) pathway analysis and evaluation of gene expression data in patient databases. Results: MicroRNA profiling of bone marrow samples at diagnosis and after relapse revealed significant differential expression of a large number of microRNAs between the two time points. Subsequent GO pathway analysis identified 11 signal transduction pathways likely to be affected by the differential miRNA signatures. Exemplary validation of the FoxO signaling pathway by gene expression analysis confirmed significant upregulation of FOXO1 and the target genes GADD45 and SOD2. Conclusions: Here, we show how a microRNA-based pathway prediction strategy can be used to identify differentially regulated signaling pathways that represent potential targets for therapeutic intervention.

Keywords:  acute myeloid leukemia; chemoresistance; microRNAs

DOI:  https://doi.org/10.3390/genes15121625
Blood Cancer J. 2025 Jan 09. 15(1): 3

Tunneling nanotubes between bone marrow stromal cells support transmitophagy and resistance to apoptosis in myeloma.

Antonio Giovanni Solimando, Francesco Di Palma, Vanessa Desantis, Angelo Vacca, Maria Svelto, Francesco Pisani.

DOI: https://doi.org/10.1038/s41408-025-01210-2
Elife. 2025 Jan 10. pii: e75393. [Epub ahead of print]14

Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.

Shixuan Liu, Ceryl Tan, Chloe Melo-Gavin, Miriam B Ginzberg, Ron Blutrich, Nish Patel, Michael Rape, Kevin G Mark, Ran Kafri.

  Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.75393
Cancer Discov. 2025 Jan 07.

Chronic viral mimicry induction following p53 loss promotes immune evasion.

Charles A Ishak, Sajid A Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M Gonzaga, Melanie Peralta, Ilinca M Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran Austin, Peter J B Sabatini, Benjamin D Greenbaum, Catherine A O'Brien, Trevor G Shepherd, Ming Sound Tsao, Katherine B Chiappinelli, Amit M Oza, Blaise A Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D De Carvalho.

Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through 'viral mimicry' responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0094
Biol Imaging. 2024 ;4 e11

Topology-based segmentation of 3D confocal images of emerging hematopoietic stem cells in the zebrafish embryo.

G Nardi, L Torcq, A A Schmidt, J-C Olivo-Marin.

  We develop a novel method for image segmentation of 3D confocal microscopy images of emerging hematopoietic stem cells. The method is based on the theory of persistent homology and uses an optimal threshold to select the most persistent cycles in the persistence diagram. This enables the segmentation of the image's most contrasted and representative shapes. Coupling this segmentation method with a meshing algorithm, we define a pipeline for 3D reconstruction of confocal volumes. Compared to related methods, this approach improves shape segmentation, is more ergonomic to automatize, and has fewer parameters. We apply it to the segmentation of membranes, at subcellular resolution, of cells involved in the endothelial-to-hematopoietic transition (EHT) in the zebrafish embryos.

Keywords:  3D segmentation; cell evolution; meshing; morphogenesis; persistent homology

DOI:  https://doi.org/10.1017/S2633903X24000102
Ann Hematol. 2025 Jan 04.

Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma.

Han Yu, Chengli Wu, Jie He, Yajun Zhang, Qiqi Cao, Hongyan Lan, Hongshan Li, Chengyang Xu, Chen Chen, Rong Li, Bo Zheng.

  Multiple myeloma(MM) remains incurable with high relapse and chemoresistance rates. Differentially expressed genes(DEGs) between newly diagnosed myeloma and secondary plasma cell leukemia(sPCL) were subjected to a weighted gene co-expression network analysis(WGCNA). Drug resistant myeloma cell lines were established. Seahorse XF analyzer was applied to detect the metabolism reprogramming associated with the hub gene. The metabolic relevance and the underlying mechanism of the hub gene in myeloma resistance were explored via in vitro experiments. A total of 1310 DEGs were used to construct five co-expression modules. Gene function enrichment analysis demonstrated that candidate hub genes were closely related to oxidative phosphorylation. We performed prognostic analysis and identified PSMA4 as the key hub gene related to the extramedullary invasion of myeloma. The in vitro experiments demonstrated bortezomib resistant myeloma cell lines exhibited high PSMA4 expression, improved oxidative phosphorylation activity with increased ROS level. PSMA4 knockdown re-sensitize resistant myeloma cells via suppressing oxidative phosphorylation activity. Further investigation revealed that PSMA4 induced a hypoxia state which activated the HIF-1α signaling pathway. PSMA4 induces metabolic reprogramming by improving oxidative phosphorylation activity which accounts for the hypoxia state in myeloma cell. The activated HIF-1α signaling pathway causes bortezomib resistance via promoting anti-apoptotic activity in myeloma.

Keywords:  Bortezomib resistance; Metabolic reprogramming; Myeloma; WGCNA

DOI:  https://doi.org/10.1007/s00277-024-06163-3
Exp Hematol. 2025 Jan 03. pii: S0301-472X(25)00004-9. [Epub ahead of print] 104713

Human Pluripotent Stem Cell-Derived Hematopoietic Progenitors and Mature Cells.

Christopher Sturgeon, Eirini Papapetrou, Shannon McKinney-Fridman.

DOI: https://doi.org/10.1016/j.exphem.2025.104713
Nat Commun. 2025 Jan 08. 16(1): 510

PTMNavigator: interactive visualization of differentially regulated post-translational modifications in cellular signaling pathways.

Julian Müller, Florian P Bayer, Mathias Wilhelm, Maximilian G Schuh, Bernhard Kuster, Matthew The.

Post-translational modifications (PTMs) play pivotal roles in regulating cellular signaling, fine-tuning protein function, and orchestrating complex biological processes. Despite their importance, the lack of comprehensive tools for studying PTMs from a pathway-centric perspective has limited our ability to understand how PTMs modulate cellular pathways on a molecular level. Here, we present PTMNavigator, a tool integrated into the ProteomicsDB platform that offers an interactive interface for researchers to overlay experimental PTM data with pathway diagrams. PTMNavigator provides ~3000 canonical pathways from manually curated databases, enabling users to modify and create custom diagrams tailored to their data. Additionally, PTMNavigator automatically runs kinase and pathway enrichment algorithms whose results are directly integrated into the visualization. This offers a comprehensive view of the intricate relationship between PTMs and signaling pathways. We demonstrate the utility of PTMNavigator by applying it to two phosphoproteomics datasets, showing how it can enhance pathway enrichment analysis, visualize how drug treatments result in a discernable flow of PTM-driven signaling, and aid in proposing extensions to existing pathways. By enhancing our understanding of cellular signaling dynamics and facilitating the discovery of PTM-pathway interactions, PTMNavigator advances our knowledge of PTM biology and its implications in health and disease.

DOI: https://doi.org/10.1038/s41467-024-55533-y