bims-scepro 2025-04-13 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–04–13
29 papers selected by
William Grey, University of York

Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.
Bcl7b and Bcl7c Subunits of BAF Chromatin Remodeling Complexes are Largely Dispensable for Hematopoiesis.
Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging.
Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system.
Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells.
Old hematopoietic stem cells retain competence to reconstitute a youthful B cell system that is highly responsive to protein-based vaccination.
Elastic properties of leukemic cells linked to maturation stage and integrin activation.
TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.
Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
Pyrroloquinoline Quinone Reprograms the Single-Cell Landscape of Immune Aging in Hematopoietic Immune System.
Interferon regulatory factor 4 mediates nonenzymatic IRE1 dependency in multiple myeloma cells.
Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.
Identification of CD84 as a potent survival factor in acute myeloid leukemia.
The oligosaccharyltransferase complex is an essential component of multiple myeloma plasma cells.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment.
A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML.
LRP8-dependent cholesterol metabolism modulates mTORC1 signaling and apoptotic pathways in multiple myeloma.
Cell polarity: cell type-specific regulators, common pathways, and polarized vesicle transport.
Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.
Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo.
Reduced incidence of relapse and graft-versus-host disease in acute myeloid leukemia after allogeneic hematopoietic cell transplantation.
Interferon-γ-mediated selective inhibition of hematopoiesis and the clonal advantage of HLA-lacking hematopoietic stem progenitor cells in aplastic anemia.
Noncoding RNA, ncRNA-a3, Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis.
Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.
Cancer Drug Bortezomib, a Proteasomal Inhibitor, Triggers Cytotoxicity in Microvascular Endothelial Cells via Multi-Organelle Stress.
Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
Inflammatory signaling pathways play a role in SYK inhibitor resistant AML.
QuickProt: A bioinformatics and visualization tool for DIA and PRM mass spectrometry-based proteomics datasets.

Blood Adv. 2025 Apr 06. pii: bloodadvances.2024014965. [Epub ahead of print]

Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes.

Martina Sarchi, Courtnee A Clough, Anna Gallì, Cristina Picone, Beatrice Ferrari, Edie I Crosse, Laura D Baquero Galvis, Claudia Fiducioso, Nelli Aydinyan, J Philip Creamer, Sara Pozzi, Elisabetta Molteni, Chiara Elena, Robert K Bradley, Luca Malcovati, Sergei Doulatov.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders driven by heterogeneous genetic alterations leading to variable clinical course. MDS with splicing factor SF3B1 mutations is a distinct subtype with a favorable outcome. However, selected co-mutations induce poor prognosis and how these genetic lesions cooperate in human hematopoietic stem and progenitor cells (HSPCs) during disease progression is still unclear. Here, we integrated clinical and molecular profiling of patients with SF3B1 mutations with gene editing of primary and iPSC-derived human HSPCs to show that high-risk co-mutations impart distinct effects on lineage programs of SF3B1-mutant HSPCs. Secondary RUNX1 or STAG2 mutations were clinically associated with advanced disease and reduced survival. However, RUNX1 and STAG2 mutations induced opposing regulation of myeloid transcriptional programs and differentiation in SF3B1-mutant HSPCs. Moreover, high-risk RUNX1 and STAG2, but not low-risk TET2, mutations expanded distinct SF3B1-mutant HSPC subpopulations. These findings provide evidence that progression from low- to high-risk MDS involves distinct molecular and cellular routes depending on co-mutation patterns.

DOI: https://doi.org/10.1182/bloodadvances.2024014965
Exp Hematol. 2025 Apr 03. pii: S0301-472X(25)00060-8. [Epub ahead of print] 104769

Bcl7b and Bcl7c Subunits of BAF Chromatin Remodeling Complexes are Largely Dispensable for Hematopoiesis.

Pierre Priam, Veneta Krasteva, Alexandre Polsinelli, Laurence Côté, Francis Dilauro, Thérèse-Marie Poinsignon, Pierre Thibault, Julie A Lessard.

  Chromatin remodelers have emerged as prominent regulators of hematopoietic cell development and potential drivers of various human hematological malignancies. ATP-dependent BAF chromatin remodeling complexes, related to yeast SWI/SNF, determine gene expression programs and consequently contribute to the self-renewal, commitment, and lineage-specific differentiation of hematopoietic stem cells and progenitors. Here, we investigated the elusive biological function of the core Bcl7b and Bcl7c subunits of BAF complexes in hematopoietic tissue. Our analysis of mouse constitutive knockout alleles revealed that both Bcl7b and Bcl7c are dispensable for animal survival and steady-state adult hematopoiesis. Bcl7b and Bcl7c double knockout (dKO) mice can maintain long-term hematopoiesis with no observable effect on the hematopoietic stem cell (HSC) compartment. Moreover, we show that Bcl7b/Bcl7c dKO HSCs are capable of normal multi-lineage hematopoietic reconstitution after competitive serial transplantation. Collectively, these studies suggest that the Bcl7b and Bcl7c subunits of BAF complexes are dispensable for normal hematopoiesis.

Keywords:  BAF complexes; Bcl7b; Bcl7c; chromatin remodeling; hematopoiesis

DOI:  https://doi.org/10.1016/j.exphem.2025.104769
Sci Immunol. 2025 Apr 11. 10(106): eadr2041

Bcl11a maintains hematopoietic stem cell function but accelerates inflammation-driven exhaustion during aging.

Jing Wang, Linlin Zhang, Xinyu Cui, Xiang Xu, Rui Guo, Kairui Li, Li Zhang, Bing Xu, Cizhong Jiang, Yong Yu.

Preserving hematopoietic stem cell (HSC) functionality is essential for maintaining healthy blood and the immune system throughout life. HSC function declines with age; however, the underlying mechanisms are not fully understood. Using an inducible mosaic mouse model to overexpress the transcription factor Bcl11a in the hematopoietic compartment, we found that an aging-related increase in Bcl11a mitigated HSC functional decline, promoted IL-1β production in the bone marrow (BM), and accelerated HSC attrition in a non-cell-autonomous manner. Aging-related inflammation in the BM enhanced Bcl11a and Fc receptor (FcR) expression in HSCs, and FcR signaling induced HSC differentiation. This was counteracted by Bcl11a through repression of Fcer1g. Bcl11a up-regulation promoted IL-1β production in BM myeloid cells, driving inflammation and HSC deterioration. Deletion of Fcer1g, or blocking IL-1β signaling, eliminated this non-cell-autonomous effect on HSC decline. These findings demonstrate that Bcl11a plays a dual role in HSCs during aging not only by cell-intrinsically preserving HSC function but also by promoting BM inflammation and HSC dysfunction.

DOI: https://doi.org/10.1126/sciimmunol.adr2041
Int J Biochem Cell Biol. 2025 Apr 08. pii: S1357-2725(25)00040-8. [Epub ahead of print] 106773

Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system.

Sumit Mallick, Vanya Kadla Narayana, Akhila Balakrishna Rai, Shubham Sukerndeo Upadhyay, Thottethodi Subrahmanya Keshava Prasad, Sudheer Shenoy P, Bipasha Bose.

  Cancer stem cells (CSCs) hold a significant role in cancer metastasis, high mortality and severity responsible for therapy resistance and tumour recurrence. The 26S proteasome system plays a major role in protein degradation in normal cells. As most cancers have upregulated 26S proteasome machinery, cancer cells use the 26S proteasome system in their favour for growth support by degrading unwanted proteins, but dysfunction of the 26S proteasome system induces apoptosis in cells. Here, we used hematopoietic stem cells (HSCs) and HSCs-derived conditioned media (CM) to target colorectal cancer stem cells (CRC-CSCs). HSCs are otherwise used extensively to save the lives of patients suffering from hematological malignancies and inherited blood disorders. HSCs-derived conditioned media contains various cytokines, chemokines, and secretory small molecules, which can also target the CRC-CSCs. Moreover, HSCs have exhibited CRC-CSC tropism in vitro in our pilot studies. As therapeutic uses of HSCs for targeting colorectal cancer (CRC) have never been reported, we hypothesized the CRC-CSC targeting properties of HSCs. Our results indicated altered protein function of CRC-CSCs upon co-culture with HSCs. Proteomics approaches showed that HSCs-CM disrupted 26S proteasomal complex and altered the mitochondrial bioenergetics, thereby activating apoptosis in CRC-CSCs. Furthermore, we observed that HSCs-CM significantly induced double-stranded DNA damage and proteasomal degradation, leading to apoptosis and upregulating the autophagy system. This study, hence, provides the prospective targeting of cancer stem cells using HSCs-CM, indicating a possible therapeutic approach.

Keywords:  26S proteasome; HSP; Hematopoietic stem cells; Tropism; autophagy; cancer stem cells; colorectal cancer; conditioned media; proteomics

DOI:  https://doi.org/10.1016/j.biocel.2025.106773
Leukemia. 2025 Apr 10.

Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells.

Cheng Xing, Huifang Zhang, Mengqiu Zheng, Qian Lu, Yujia Tao, Shina Xu, Yang Xiao, Long Liang, Haodong Xu, Shuqian Xu, Hongling Peng, Yue Sheng.

DOI: https://doi.org/10.1038/s41375-025-02568-9
Immun Ageing. 2025 Apr 05. 22(1): 14

Old hematopoietic stem cells retain competence to reconstitute a youthful B cell system that is highly responsive to protein-based vaccination.

Paul Kunath, Dominik Pflumm, Bettina Moehrle, Vadim Sakk, Alina Seidel, Jan Münch, Hartmut Geiger, Reinhold Schirmbeck.

   BACKGROUND: Ageing-associated remodeling of the murine B cell system is accompanied with a reduction of CD19+ B cells such as follicular B cells (FOB) and an accumulation of age-associated B cells (ABC) or activated B cell subsets. This remodeling is thought to confer an attenuated antibody response, such as to SARS-CoV-2 spike (S) vaccines in both aged mice and humans. To gain insight into the de novo development and function of an old B cell system, we reconstituted young and old immune systems by transferring hematopoietic stem cells (HSCs) from immune-competent young (2-3 months) CD45.1+ donors (DY-HSC) or old (20-24 months) donors (DO-HSC) into T and B cell-deficient young recipient CD45.2+ RAG1-/- mice, followed by protein-based vaccination.
RESULTS: In the same environment of young RAG1-/- mice, transplanted DO-HSCs compared to DY-HSCs reconstituted lower numbers of CD19+ B cells and CD45.1+ cells, though the engraftment of donor-derived HSCs in the young bone marrow (BM) was very similar. Furthermore, indicative for youthful and unchallenged B cell systems, and in contrast to aged mice, very low levels of antigen-experienced memory B cells or age-associated B cells (ABC) developed in both DY-HSC and DO-HSC hosts. The commercially available recombinant SARS-CoV-2 S vaccine (NVX-CoV2373) induced lower IgG+ S-antibody titers and pseudovirus neutralization activity in old compared to young mice. In contrast, very similar high IgG+ S-antibody titers were induced in DO-HSC and DY-HSC hosts, and pseudovirus neutralization activity was even enhanced in DO-HSC compared with DY-HSC hosts.
CONCLUSIONS: Both DO-HSCs and DY-HSCs established in the young recipient BM to a similar extend, suggesting that the concomitant reduction in the de novo reconstitution of CD19+ B cells in DO-HSC vs. DY-HSC transplanted animals is specifically related to old HSCs. DO-HSCs and DY-HSCs reconstitute very similar unchallenged B cell systems that efficiently elicit antigen-specific IgG antibodies by protein-based vaccination. Old HSCs thus retain competence to reconstitute a youthful and functional B cell system, at least in the young environment of transplanted RAG1-/- mice. This suggests that it is primarily age-related factors, and not HSCs per se, that influence the composition and functionality of the old B cell system.

Keywords:  B cells; Hematopoietic stem cells; IgG antibody response; Old immune system; SARS-CoV-2 spike vaccine

DOI:  https://doi.org/10.1186/s12979-025-00507-x
iScience. 2025 Apr 18. 28(4): 112150

Elastic properties of leukemic cells linked to maturation stage and integrin activation.

Ceri J Richards, Albertus T J Wierenga, Annet Z Brouwers-Vos, Emmanouil Kyrloglou, Laura S Dillingh, Patty P M F A Mulder, Georgios Palasantzas, Jan Jacob Schuringa, Wouter H Roos.

  Acute myeloid leukemia (AML) remains challenging to cure. In addition to mutations that alter cell functioning, biophysical properties are modulated by external cues. In particular, membrane proteins that interact with the bone marrow niche can induce cellular changes. Here, we develop an atomic force microscopy (AFM) approach to measure non-adherent AML cell mechanical properties. The Young's modulus of the AML cell line, THP-1, increased in response to retronectin, whereas knock-out of the adhesion protein ITGB1 resulted in no response to retronectin. Confocal microscopy revealed different actin cytoskeleton morphologies for wild-type and ITGB1 knock-out cells exposed to retronectin. These results indicate that ITGB1 mediates stimuli-induced cellular mechanoresponses through cytoskeletal changes. We next used AFM to investigate the elastic properties of primary AML cells and found that more committed cells had lower Young's moduli than immature AMLs. Overall, this provides a platform for investigating the molecular mechanisms involved in leukemic cell mechanoresponse.

Keywords:  Biomechanics; Health sciences; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2025.112150
bioRxiv. 2025 Mar 27. pii: 2025.03.24.644993. [Epub ahead of print]

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.

Jeevitha D'Souza, Camille J Leung, Aishwarya C Ballapuram, Abigail S Lin, Alexa Rane Batingana, Adam J Lamble, Rhonda E Ries, Carolina E Morales, Charisa Cottonham, Pranav Gona, Li Fan, Xiaotu Ma, Kevin Shannon, Soheil Meshinchi, Benjamin S Braun, Benjamin J Huang.

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.

DOI: https://doi.org/10.1101/2025.03.24.644993
bioRxiv. 2025 Mar 26. pii: 2025.03.24.645017. [Epub ahead of print]

Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.

Gaurav Agarwal, Mateusz Antoszewski, Xueqin Xie, Yash Pershad, Uma P Arora, Chi-Lam Poon, Peng Lyu, Andrew J Lee, Chun-Jie Guo, Tianyi Ye, Laila Barakat Norford, Anna-Lena Neehus, Lucrezia Della Volpe, Lara Wahlster, Diyanath Ranasinghe, Tzu-Chieh Ho, Trevor S Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, Benjamin H Durham, Omar Abdel-Wahab, Kathy L McGraw, James M Allan, Ruslan Soldatov, Alexander G Bick, Michael G Kharas, Vijay G Sankaran.

Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.

DOI: https://doi.org/10.1101/2025.03.24.645017
Aging Cell. 2025 Apr 07. e70050

Pyrroloquinoline Quinone Reprograms the Single-Cell Landscape of Immune Aging in Hematopoietic Immune System.

Xiuxing Liu, Chun Zhang, Jianjie Lv, Yidan Liu, Chenyang Gu, Yuehan Gao, Wen Ding, Hui Chen, Nanwei Xu, Hongbin Yin, Wenru Su, Zhuping Xu.

  Aging is an inevitable biological process, driven in part by increased oxidative stress, which accelerates cellular damage and contributes to immune system dysfunction. Therefore, targeting oxidative stress has emerged as a potential strategy. Pyrroloquinoline quinone (PQQ), a potent antioxidant, has demonstrated significant efficacy in reducing oxidative stress and modulating immune responses, making it a promising therapeutic candidate. In this study, we investigated the effects of aging on the hematopoietic immune system (HIS) through single-cell RNA sequencing (scRNA-seq) of spleen and bone marrow cells in murine models. Our results revealed widespread age-related inflammation and oxidative stress within immune cell populations. Notably, long-term PQQ supplementation improved physiological parameters and reduced blood inflammatory factors levels in aged mice. Subsequent scRNA-seq analysis demonstrated that PQQ supplementation effectively reduced oxidative stress levels across various HIS cell types and reversed aging-related phenotypes, such as inflammatory responses and immunosenescence. Additionally, PQQ reversed aging-induced disrupted signaling and restored immune homeostasis, particularly in B cells and hematopoietic stem cells (HSCs). Importantly, we identified critical molecular targets, including ASPP1, which mediates PQQ's anti-apoptotic effects in B cells, and Yy1 and CD62L, which were upregulated by PQQ to restore HSCs self-renewal and differentiation potential. Furthermore, the machine learning program and experimental validation demonstrated the senolytic and senomorphic effects of PQQ in vivo and vitro. These findings underscore PQQ's potential not only in mitigating oxidative stress but also in restoring immune homeostasis and promoting cellular regeneration, highlighting its therapeutic potential in addressing immune aging and improving physiological function.

Keywords:  aging; hematopoietic immune system; oxidative stress; pyrroloquinoline quinone; senescent cells

DOI:  https://doi.org/10.1111/acel.70050
PLoS Biol. 2025 Apr 11. 23(4): e3003096

Interferon regulatory factor 4 mediates nonenzymatic IRE1 dependency in multiple myeloma cells.

Ioanna Oikonomidi, Vasumathi Kameswaran, Victoria C Pham, Iratxe Zuazo-Gaztelu, Lauren M Gutgesell, Scot Marsters, Bence Daniel, Jennie R Lill, Zora Modrusan, Avi Ashkenazi.

Multiple myeloma (MM) arises through oncogenic transformation of immunoglobulin-secreting plasma cells. MM often co-opts the central endoplasmic reticulum (ER)-stress mitigator, inositol-requiring enzyme 1 (IRE1), to sustain malignant growth. While certain MMs require enzymatic IRE1-dependent activation of the transcription factor XBP1s, others display a nonenzymatic IRE1 dependency that is not yet mechanistically understood. Here we identify interferon regulatory factor 4 (IRF4), which stimulates genes that promote immune-cell proliferation, as a key conduit for IRE1's nonenzymatic control of cell-cycle progression in MM. IRE1 silencing increased inhibitory S114/S270 phosphorylation on IRF4, disrupting IRF4's chromatin-binding and transcriptional activity. IRF4 knockdown recapitulated, whereas IRF4 repletion reversed the anti-proliferative phenotype of IRE1 silencing. Furthermore, phospho-deficient, but not phospho-mimetic, IRF4 mutants rescued proliferation under IRE1 silencing. Functional studies revealed that IRF4 engages the E2F1 and CDC25A genes and promotes CDK2 activation to drive cell-cycle progression. Our results advance mechanistic understanding of IRE1 and IRF4 in MM.

DOI: https://doi.org/10.1371/journal.pbio.3003096
Oncogenesis. 2025 Apr 11. 14(1): 9

Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.

Oded Komemi, Elina Orbuch, Osnat Jarchowsky-Dolberg, Yaron Shraga Brin, Shelly Tartakover-Matalon, Metsada Pasmanik-Chor, Michael Lishner, Liat Drucker.

Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells' bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (SRC), mitochondrial fusion and UPRmt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and SRC. Targeting MM-MSC' SRC with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.

DOI: https://doi.org/10.1038/s41389-025-00554-5
J Clin Invest. 2025 Apr 08. pii: e176818. [Epub ahead of print]

Identification of CD84 as a potent survival factor in acute myeloid leukemia.

Yinghui Zhu, Mariam Murtadha, Miaomiao Liu, Enrico Caserta, Ottavio Napolitano, Le Xuan Truong Nguyen, Huafeng Wang, Milad Moloudizargari, Lokesh Nigam, Theophilus Tandoh, Xuemei Wang, Alex Pozhitkov, Rui Su, Xiangjie Lin, Marc Denisse Estepa, Raju Pillai, Joo Song, James F Sanchez, Yu-Hsuan Fu, Lianjun Zhang, Man Li, Bin Zhang, Ling Li, Ya-Huei Kuo, Steven Rosen, Guido Marcucci, John C Williams, Flavia Pichiorri.

  Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provided a survival advantage to leukemia cells, whereas CD84 downregulation disrupted their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulated leukemia cells' energy metabolism and mitochondrial dynamics. Depletion of CD84 altered mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing AML antioxidant defense. Conversely, CD84 over-expression stabilized NRF2 and promoted its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicated that AML cells depend on CD84 to support antioxidant pro-survival pathways, highlighting a therapeutic vulnerability of leukemia cells.

Keywords:  Antigen; Bone marrow; Cancer immunotherapy; Cell biology; Hematology; Oncology

DOI:  https://doi.org/10.1172/JCI176818
Mol Ther Oncol. 2025 Jun 18. 33(2): 200964

The oligosaccharyltransferase complex is an essential component of multiple myeloma plasma cells.

Hong Phuong Nguyen, Enze Liu, Anh Quynh Le, Mahesh Lamsal, Jagannath Misra, Sankalp Srivastava, Harikrishnan Hemavathy, Reuben Kapur, Mohammad Abu Zaid, Rafat Abonour, Ji Zhang, Ronald C Wek, Brian A Walker, Ngoc Tung Tran.

  Multiple myeloma (MM) is an incurable malignancy characterized by mutated plasma cell clonal expansion in the bone marrow, leading to severe clinical symptoms. Thus, identifying new therapeutic targets for MM is crucial. We identified the oligosaccharyltransferase (OST) complex as a novel vulnerability in MM cells. Elevated expression of this complex is associated with relapsed, high-risk MM, and poor prognosis. Disrupting the OST complex suppressed MM cell growth, induced cell-cycle arrest, and apoptosis. Combined inhibition with bortezomib synergistically eliminated MM cells in vitro and in vivo, via suppressing genes related to bortezomib-resistant phenotypes. Mechanistically, OST complex disruption downregulated MM pathological pathways (mTORC1 pathway, glycolysis, MYC targets, and cell cycle) and induced TRAIL-mediated apoptosis. Notably, MYC translation was robustly suppressed upon inhibiting the OST complex. Collectively, the OST complex presents a novel target for MM treatment, and combining its inhibition with bortezomib offers a promising approach for relapsed MM patients.

Keywords:  MT: Regular Issue; MYC translation; N-glycosylation; apoptosis; bortezomib resistance; cell-cycle arrest; mTOCR1 pathway; multiple myeloma; oligosaccharyltransferase complex; post-translational modification; relapsed/refractory myeloma; xenograft model

DOI:  https://doi.org/10.1016/j.omton.2025.200964
Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Cells. 2025 Mar 21. pii: 474. [Epub ahead of print]14(7):

c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment.

Naoki Osada, Jiro Kikuchi, Sae Matsuoka, Hiroshi Yasui, Sho Ikeda, Naoto Takahashi, Yusuke Furukawa, Hideki Nakasone.

  Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD.

Keywords:  bone marrow microenvironment; c-FOS; cancer stem cell; drug resistance; multiple myeloma

DOI:  https://doi.org/10.3390/cells14070474
Drug Resist Updat. 2025 Mar 28. pii: S1368-7646(25)00042-1. [Epub ahead of print]81 101242

A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML.

Elahe Rahimian, Masoud Koochak, Sofia Traikov, Michael Schroeder, Silke Brilloff, Silvia Schäfer, Vida Kufrin, Sandra Küchler, Alexander Krüger, Peter Mirtschink, Gustavo Baretton, Evelin Schröck, Denis M Schewe, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Marius Bill, Alexander A Wurm.

  Relapse in acute myeloid leukemia (AML) is driven by resistant subclones that survive chemotherapy. It is assumed that these resilient leukemic cells can modify their proliferative behavior by entering a quiescent-like state, similar to healthy hematopoietic stem cells (HSCs). These dormant cells can evade the effects of cytostatic drugs that primarily target actively dividing cells. Although quiescence has been extensively studied in healthy hematopoiesis and various solid cancers, its role in AML has remained unexplored. In this study, we applied an HSC-derived quiescence-associated gene signature to an AML patient cohort and found it to be strongly correlated with poor prognosis and active TGF-β signaling. In vitro treatment with TGF-β1 induces a quiescence-like phenotype, resulting in a G0 shift and reduced sensitivity to cytarabine. To find potential therapeutic targets that prevent AML-associated quiescence and improve response to cytarabine, we conducted a comprehensive CRISPR interference (CRISPRi) screen combined with TGF-β1 stimulation. This approach identified TGFBR1 inhibitors, like vactosertib, as effective agents for preventing the G0 shift in AML cell models. However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. To elucidate the underlying mechanism, we performed a multi-faceted approach combining a second CRISPRi screen, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and in silico analysis. Our findings revealed that TGFBR1 inhibitors unintentionally target the nucleoside transporter SLC29A1 (ENT1), leading to reduced intracellular cytarabine levels. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment.

Keywords:  AML; Chemoresistance; Kinase inhibitors; Nucleoside transporter ENT1; Quiescence; TGF-β signaling pathway; Vactosertib

DOI:  https://doi.org/10.1016/j.drup.2025.101242
Cell Death Dis. 2025 Apr 08. 16(1): 263

LRP8-dependent cholesterol metabolism modulates mTORC1 signaling and apoptotic pathways in multiple myeloma.

Yue Wang, Tianwei Lan, Chi Zhou, Qiongyan Zhang, Peng Liu.

Cholesterol plays a crucial role in tumor metabolism. Studies have shown that the serum cholesterol level of multiple myeloma (MM) patients significantly decreases, probably owing to the augmented uptake by MM cells. Despite its significance for MM, research on its metabolism within MM is limited. Our analysis of clinical data from 703 newly diagnosed MM patients revealed that low serum cholesterol is associated with poor prognosis, and it stems from the elevated cholesterol consumption by MM cells. By exploring the transcriptome and single-cell RNA-seq data of patients with different cholesterol levels in our center, we identified LRP8 as a key regulator of cholesterol metabolism in MM, which is closely related to prognosis and disease stages. We verified the oncogenic role of LRP8 in vitro and in vivo. Knockdown of LRP8 can facilitate apoptosis and cell cycle arrest in MM cells. Meanwhile, we employed mouse xenograft tumor model to replicate the phenomenon that MM cells with high LRP8 expression consume cholesterol, causing low serum cholesterol. Mechanistically, high LRP8 expression enhances cholesterol utilization and uptake by MM cells; LRP8 inhibition reduces cholesterol absorption, further weakening the activity of the cholesterol-dependent mTORC1 pathway in MM cells and inducing apoptosis. Concurrently, it triggers an upregulation of protective autophagy. Further suppression of autophagy can lead to extensive apoptosis of MM cells. Our study reveals that LRP8 regulates cholesterol metabolism in MM cells and influences the processes of cell apoptosis and autophagy through metabolic-related pathways. LRP8 holds potential as a therapeutic target for MM.

DOI: https://doi.org/10.1038/s41419-025-07625-w
Leukemia. 2025 Apr 09.

Cell polarity: cell type-specific regulators, common pathways, and polarized vesicle transport.

Soumen Bera, Dirk Loeffler.

Cell polarity, the asymmetric organization of cellular components, is evolutionarily conserved from unicellular and multicellular organisms and is crucial for many biological processes. Polarity is required to maintain cell and tissue integrity by regulating cell division, migration, orientation, cell-cell interactions, and morphogenesis. Impaired polarity leads to dysregulation of cellular functions and is associated with disease. Understanding how polarity is established, maintained, and regulated is thus critical to improving our knowledge of pathologies and devising novel therapies. Here, we explore the various manifestations of cell polarity across different model systems, tissues, and cell types and focus on known polarity mechanisms in hematopoietic stem and progenitor cells. We discuss how cells with vastly different functions utilize conserved molecular complexes to establish cell polarity while adapting polarity proteins to unique cell-type-specific functions. In this discussion, we attempt to extract common themes and concepts to improve our understanding of cell polarity in hematological malignancies and other diseases. Finally, we summarize, compare, and evaluate classical as well as recently developed methods to quantify cell polarity, highlight important advances in imaging and analytical techniques, and suggest critical next steps required to move the field forward.

DOI: https://doi.org/10.1038/s41375-025-02601-x
Nat Commun. 2025 Apr 11. 16(1): 3450

Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes.

Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome McAllen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla.

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.

DOI: https://doi.org/10.1038/s41467-025-58662-0
Nat Commun. 2025 Apr 11. 16(1): 3480

Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo.

Natasha M Nesbitt, Gian Luca Araldi, Lisa Pennacchia, Natalia Marchenko, Zahra Assar, Kendall M Muzzarelli, Rahul Raghavan Thekke Veedu, Brian Medel-Lacruz, Eunjeong Lee, Elan Z Eisenmesser, Dale F Kreitler, Wadie F Bahou.

Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening of unique small molecules retaining the capacity for selective BLVRB inhibition as a novel platelet-enhancing strategy. Two distinct classes of molecules are identified, and NMR spectroscopy and co-crystallization studies confirm binding modes within the BLVRB active site and ring stacking between the nicotinamide moiety of the NADP+ cofactor. A diazabicyclo derivative displaying minimal off-target promiscuity and excellent bioavailability characteristics promotes megakaryocyte speciation in biphenotypic (erythro/megakaryocyte) cellular models and synergizes with TPO-dependent megakaryocyte formation in hematopoietic stem cells. Upon oral delivery into mice, this inhibitor expands platelet recovery in stress thrombopoietic models with no adverse effects. In this work, we identify and validate a cellular redox inhibitor retaining the potential to selectively promote megakaryocytopoiesis and enhance stress-associated platelet formation in vivo distinct from TPO receptor agonists.

DOI: https://doi.org/10.1038/s41467-025-58497-9
Haematologica. 2025 Apr 10.

Reduced incidence of relapse and graft-versus-host disease in acute myeloid leukemia after allogeneic hematopoietic cell transplantation.

Haesook T Kim, Robert J Soiffer, Corey Cutler, John Koreth, Sarah Nikiforow, Roman M Shapiro, Amar Kelkar, Mahasweta Gooptu, Rizwan Romee, Catherine J Wu, Joseph H Antin, Jerome Ritz, Vincent T Ho.

Advances in HLA typing, conditioning regimens, GVHD prophylaxis/treatment, and supportive care have led to significant improvement in survival after allogeneic hematopoietic cell transplantation (alloHCT). Despite this progress, disease relapse after transplantation remains a daunting challenge and continues to be a major driver of mortality in patients with acute myeloid leukemia (AML). To assess whether progress has been made in relapse, we investigated our institution's experience with all AML patients who underwent their first allogeneic transplants from 2010 through 2022. A total of 1169 patients were identified. The year of transplant was divided into two groups: 2010-2016 and 2017-2022. Several shifts in baseline clinical characteristics were noted during these periods. Patients who underwent transplantation in 2017-2022 were older (p.

DOI: https://doi.org/10.3324/haematol.2025.287390
Leukemia. 2025 Apr 11.

Interferon-γ-mediated selective inhibition of hematopoiesis and the clonal advantage of HLA-lacking hematopoietic stem progenitor cells in aplastic anemia.

Rio Takahashi, Honoka Takahashi, Luna Seoka, Hiroka Iwasaki, Hiroyuki Takamatsu, Tatsuya Imi, Yoshitaka Zaimoku, Kohei Hosokawa, Takamasa Katagiri.

Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure caused by autoreactive cytotoxic T lymphocytes targeting hematopoietic stem progenitor cells (HSPCs). Approximately 30% of AA patients exhibit leukocytes lacking HLA class I alleles (HLA[-]). In addition to this direct immune assault, the pathogenesis of AA is thought to involve indirect suppression mediated by the proinflammatory cytokine interferon-gamma (IFN-γ). Using HSPCs derived from induced pluripotent stem cells (iPSCs) with different HLA genotypes, HLA(-) HSPCs were found to be resistant to the suppressive effects of IFN-γ, whereas IFN-γ effectively suppressed the growth and development of HSPCs expressing HLA class I molecules. Further analysis showed that, in contrast to HLA(-) HSPCs, WT HSPCs showed enhanced CD119 expression in response to IFN-γ, activating downstream signaling pathways that promote apoptosis, suggesting that transcription factors involved in the apoptotic pathway following IFN-γ stimulation are differentially expressed between WT and HLA(-) HSPCs. Notably, IFN-γ stimulation reduced the expression of pSTAT3, a key regulator of apoptosis, in WT HSPCs, whereas its expression was elevated in HLA(-) HSPCs. In conclusion, this study showed that the selective hematopoietic inhibition of HSPCs by IFN-γ likely facilitates clonal hematopoiesis and contributes to the persistence of HLA(-) HSPCs in patients with AA.

DOI: https://doi.org/10.1038/s41375-025-02595-6
Mol Cell Biol. 2025 Apr 10. 1-16

Noncoding RNA, ncRNA-a3, Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis.

Meghana Matur, Yasin Uzun, Xiangguo Shi, Karina Hamamoto, Yi Qiu, Suming Huang.

  Hematopoietic transcription is a combinatorial control of transcription factors, chromatin modifiers, and non-coding RNAs. TAL1 is a critical regulator of normal and malignant hematopoiesis. However, mechanism underlying regulation of TAL1 activity during erythropoiesis versus leukemogenesis remains elusive. Here, we showed that an enhancer RNA, ncRNA-a3 transcribed from TAL1 + 51Kb-enhancer, is positively correlated with TAL1 locus chromatin accessibility and transcription, and required for TAL1 activation during EPO-induced erythropoiesis. Loss of ncRNA-a3 in CD34+ hematopoietic stem and progenitor cells leads to reduction of TAL1 transcription, followed by impaired terminal erythroid differentiation. The effect of ncRNA-a3 loss on erythroid differentiation is partially rescued by overexpression of Tal1 cDNA, suggesting an important role of ncRNA-a3/TAL1 regulatory axis in erythropoiesis. Mechanistically, ncRNA-a3 regulates long-range chromatin interactions between +51Kb erythroid-specific enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By facilitating the binding and recruitment of p300/BRG1 to the TAL1 locus, ncRNA-a3 promotes chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid-specific TAL1 target genes. Our study reveals a novel role for ncRNA-a3 in TAL1 dependent erythropoiesis and establishes a new mode of ncRNA-a3 action in TAL1 transcriptional activation.

Keywords:  TAL1 oncogene; chromatin structure; eRNA; erythropoiesis; gene regulation

DOI:  https://doi.org/10.1080/10985549.2025.2482079
Cell. 2025 Apr 04. pii: S0092-8674(25)00282-X. [Epub ahead of print]

Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.

Andrew Murley, Ann Catherine Popovici, Xiwen Sophie Hu, Anina Lund, Kevin Wickham, Jenni Durieux, Larry Joe, Etai Koronyo, Hanlin Zhang, Naomi R Genuth, Andrew Dillin.

  To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.

Keywords:  aging; endoplasmic reticulum; lysosome; mTOR; macroautophagy; protein aggregates; quiescence

DOI:  https://doi.org/10.1016/j.cell.2025.03.009
bioRxiv. 2025 Mar 26. pii: 2025.03.25.645304. [Epub ahead of print]

Cancer Drug Bortezomib, a Proteasomal Inhibitor, Triggers Cytotoxicity in Microvascular Endothelial Cells via Multi-Organelle Stress.

Prajakta Sawant, Aleena Mathew, Johanna Bensalel, Julio Gallego-Delgado, Pratyusha Mandal.

Proteasomes maintain cellular homeostasis by degrading abnormal proteins, while cancer cells exploit them for survival, becoming a key chemotherapeutic target. Bortezomib (BTZ), a reversible proteasomal inhibitor, is a front-line treatment for multiple myeloma, mantle cell lymphoma, and non-small cell lung cancer. However, its efficacy is limited by severe side effects, including neurotoxicity and cardiovascular distress, with its toxicity mechanisms largely unexplored. Here, we discover that Bortezomib (BTZ), is cytotoxic to non-cancerous cells distinctly from Carfilzomib (CFZ), the second-line irreversible PI. BTZ or CFZ is administered intravenously, impacting blood vessel (vascular) endothelial cells. We used human pulmonary microvascular endothelial cells (HPMECs) to demonstrate that BTZ but not CFZ elicits endoplasmic reticulum (ER) stress, mitochondrial membrane compromise, mitochondrial reactive oxygen species (ROS) accumulation, and Caspase (CASP)9 activation (mediator of Intrinsic apoptosis) within fifteen hours of treatment. By twenty-four hours, BTZ-treated cells display cleavage of CASP8 (mediator of extrinsic apoptosis), activation of CASP3 (terminal executioner of apoptosis), cell-death and vascular barrier loss. Pan-caspase inhibitor zVAD significantly rescues BTZ-treated cells from cytotoxicity. Both BTZ and CFZ effectively kill MM cells. These findings reveal novel insights into fundamental signaling of regular cells where reversible inhibition of the proteasome dictates a unique cascade of stress distinct from irreversible inhibition. These harmful effects of BTZ emphasize the need to re- evaluate its use as a frontline chemotherapy for MM.
Highlights: Reversible proteasomal inhibitor Bortezomib is cytotoxic to non-cancerous, microvascular endothelial cellsIn endothelial cells, Bortezomib, but not irreversible inhibitor Carfilzomib, activates temporal cascade of caspases (Caspase-9, Caspase-8, Caspase-3) triggering apoptosisCaspase activation results from ER stress (via the IRE1α-CHOP) pathway and mitochondrial stress (ROS accumulation) independently from contribution from extrinsic signal via TNFBortezomib-dependent cytotoxicity compromises endothelial barrier potential.

DOI: https://doi.org/10.1101/2025.03.25.645304
Nat Med. 2025 Apr 07.

Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.

Raffaella Molteni, Martina Fiumara, Corrado Campochiaro, Roberta Alfieri, Guido Pacini, Eugenia Licari, Alessandro Tomelleri, Elisa Diral, Angelica Varesi, Alessandra Weber, Pamela Quaranta, Luisa Albano, Chiara Gaddoni, Luca Basso-Ricci, Davide Stefanoni, Laura Alessandrini, Sara Degl'Innocenti, Francesca Sanvito, Gregorio Maria Bergonzi, Andrea Annoni, Maddalena Panigada, Eleonora Cantoni, Daniele Canarutto, Stephanie Z Xie, Angelo D'Alessandro, Raffaella Di Micco, Alessandro Aiuti, Fabio Ciceri, Giacomo De Luca, Lorenzo Dagna, Marco Matucci-Cerinic, Ivan Merelli, Simone Cenci, Serena Scala, Giulio Cavalli, Luigi Naldini, Samuele Ferrari.

Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common nonmalignant disorders. VEXAS syndrome is a recently discovered, adult-onset, autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. In the present study, we performed immunophenotype characterization of hematopoiesis and single-cell transcriptomics in a cohort of nine male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks. Competitive transplantations of human UBA1-mutant and wild-type HSPCs showed that, although mutant cells are more resilient to the inflammatory milieu, probably through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance and provides models for preclinical studies and preliminary insights that could inform therapeutic strategies.

DOI: https://doi.org/10.1038/s41591-025-03623-9
Sci Rep. 2025 Apr 05. 15(1): 11673

Inflammatory signaling pathways play a role in SYK inhibitor resistant AML.

Sarah Tausch, Christina Villinger, Gabriela Alexe, Daniel J Urban, Min Shen, Dominique Jahn, Jonas Vischedyk, Sebastian Scheich, Hubert Serve, Matthew D Hall, Kimberly Stegmaier, Thomas Oellerich, Anjali Cremer.

  Trials have shown promising clinical activity of the selective SYK inhibitor entospletinib in patients with high expressing HOXA9/MEIS1 acute leukemias. As the development of resistance mechanisms is a common problem in the use of targeted drugs, we performed a chemical library screen to identify drug sensitivities in SYK inhibitor resistant AML cells. We identified that SYK inhibitor resistant cells displayed an increased sensitivity to glucocorticoids. Glucocorticoids are potent immunosuppressants which work in part by inhibiting the transcription of cytokine genes. RNA sequencing of entospletinib resistant cells revealed a strong enrichment of inflammatory response and TNFα signaling via NF-κB gene sets in comparison to naive cells. Naive AML cells treated with entospletinib showed a strong downregulation of the same gene sets which were upregulated in the resistant state. Our data suggest that inflammatory signaling pathways play a role in entospletinib resistant AML cells.

Keywords:  Acute myeloid leukemia cells; Glucocorticoids; Inflammatory pathways; Resistance

DOI:  https://doi.org/10.1038/s41598-025-96660-w
bioRxiv. 2025 Mar 28. pii: 2025.03.24.645047. [Epub ahead of print]

QuickProt: A bioinformatics and visualization tool for DIA and PRM mass spectrometry-based proteomics datasets.

Omar Arias-Gaguancela, Carmen Palii, Mehar Un Nissa, Marjorie Brand, Jeff Ranish.

Mass spectrometry (MS)-based proteomics focuses on identifying and quantifying peptides and proteins in biological samples. Processing of MS-derived raw data, including deconvolution, alignment, and peptide-protein prediction, has been achieved through various software platforms. However, the downstream analysis, including quality control, visualizations, and interpretation of proteomics results remains challenging due to the lack of integrated tools to facilitate the analyses. To address this challenge, we developed QuickProt, a series of Python-based Google Colab notebooks for analyzing data-independent acquisition (DIA) and parallel reaction monitoring (PRM) proteomics datasets. These pipelines are designed so that users with no coding expertise can utilize the tool. Furthermore, as open-source code, QuickProt notebooks can be customized and incorporated into existing workflows. As proof of concept, we applied QuickProt to analyze in-house DIA and stable isotope dilution (SID)-PRM MS proteomics datasets from a time-course study of human erythropoiesis. The analysis resulted in annotated tables and publication-ready figures revealing a dynamic rearrangement of the proteome during erythroid differentiation, with the abundance of proteins linked to gene regulation, metabolic, and chromatin remodeling pathways increasing early in erythropoiesis. Altogether, these tools aim to automate and streamline DIA and PRM-MS proteomics data analysis, making it more efficient and less time-consuming.

DOI: https://doi.org/10.1101/2025.03.24.645047