bims-scepro 2025-06-08 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–06–08
27 papers selected by
William Grey, University of York

Balancing Hematopoietic Stem Cell Self-renewal and Differentiation Activities Throughout Ontogeny and Aging.
Hematopoietic stem cell size heterogeneity is not linked to changes in stem cell potential of aged HSCs.
Integrative analysis of copper dysregulation and cuproptosis in postnatal hematopoiesis.
A capsular myofibroblastic niche maintains hematopoietic stem cells in the spleen.
Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.
FOXP1 contributes to murine hematopoietic stem cell functionality.
Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
Stem Cell Niche: iPSC-Based Assembloids for Modeling Human Hematopoiesis.
Clearance of protein aggregates during cell division.
AttentionAML: An Attention-based Deep Learning Framework for Accurate Molecular Categorization of Acute Myeloid Leukemia.
In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.
Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis.
Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia.
Comprehensive characterization of human bone marrow microenvironment shows age-related changes.
Targeting transcription-replication conflicts using G-quadruplexes stabilizers in multiple myeloma.
The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis.
A non-genotoxic stem cell therapy boosts lymphopoiesis and averts age-related blood diseases in mice.
Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
Active protein quality control in quiescence: involvement of proteasomes, autophagy, and nucleus-vacuole junctions.
Cheminformatic identification of small molecules targeting acute myeloid leukemia.
Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.
Blocking a cell surface protein beats AML.
An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS.
Multiplex gene editing models of del(7q) reveal combined CUX1 and EZH2 loss drives clonal expansion and drug resistance.
Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.
ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation.

Exp Hematol. 2025 May 31. pii: S0301-472X(25)00111-0. [Epub ahead of print] 104820

Balancing Hematopoietic Stem Cell Self-renewal and Differentiation Activities Throughout Ontogeny and Aging.

Masayuki Yamashita, Jingjing Li, Vu L Tran, Myriam L R Haltalli, Shannon McKinney-Freeman, Toshio Suda.

  During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging, which was the focus of the Summer 2024 International Society for Experimental Hematology (ISEH) webinar. Teaser Abstract: During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging.

Keywords:  Hematopoietic stem cells; differentiation; fetal liver; lineage tracing; mitochondrial metabolism; self-renewal

DOI:  https://doi.org/10.1016/j.exphem.2025.104820
Front Aging. 2025 ;6 1596565

Hematopoietic stem cell size heterogeneity is not linked to changes in stem cell potential of aged HSCs.

Mehmet Saçma, Ali Hageb, Alex Zadro, Tanja Schuster, Mona Vogel, Karina Eiwen, Vadim Sakk, Hartmut Geiger.

  Aging is associated with a decline in the function of hematopoietic stem cells (HSCs). This decline in HSC function results in reduced hematologic regenerative capacity and an increased incidence of hematologic disorders. In general, aged HSCs show on average an increase in cell size and a lower frequency of cells polar for protein polarity markers. The size of an HSCs has been proposed to be tightly linked to the potential of the HSCs, with small HSCs showing a higher potential compared to large HSCs. The increase in size of HSCs upon aging may be associated with the reduced potential of aged HSCs. HSCs are located within the bone marrow (BM) in distinct microenvironments called niches. These niches provide critical physical and molecular signals that are essential for HSC self-renewal, proliferation, migration and differentiation. There are multiple types of functional niches, and HSCs within these distinct types of niches show a distinct type of potential. Furthermore, the distribution of HSCs relative to niches changes upon aging. It is not known whether there is a correlation of HSCs size, HSCs polarity and the location of HSCs in distinct types of niches, as might be expected, as all three (size, polarity and position) have been linked to HSC potential. Here we show that in young mice smaller HSCs, which are more myeloid-biased, are preferentially located at central BM niches, including sinusoids and megakaryocytes. In contrast, larger HSCs, which show a bias toward B-lymphoid differentiation, are preferentially located in endosteal BM niches close to arterioles. However, in aged mice, which also contain HSCs of different sizes, there was no correlation between HSC size and localization and potential. Furthermore, within the hematopoietic stem and progenitor cell (HSPC) population, cell size increases as the cells become more limited in their capacity. Notably, we further report that changes in the level of polarity correlate with HSC potential even in aged mice.

Keywords:  aging; bone marrow niches; cell size and function; hematopoietic aging; hematopoietic stem cells; regenerative potential; stem cell differentiation; stem cell polarity

DOI:  https://doi.org/10.3389/fragi.2025.1596565
Sci Bull (Beijing). 2025 May 16. pii: S2095-9273(25)00531-6. [Epub ahead of print]

Integrative analysis of copper dysregulation and cuproptosis in postnatal hematopoiesis.

Liyun Chen, Qian Wu, Chaohui Lin, Zijun Song, Yunxing Su, Chaodong Ge, Xue Wang, Hongbing Luo, Rong Wang, Yanfang Wang, Junxia Min, Fudi Wang.

  Copper dysregulation has been linked to human health, disorders, and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of dietary copper via the transporter Slc31a1(Ctr1) in copper homeostasis, but not cuproptosis, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper uptake sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). Using transcriptomic analyses, we reveal a disrupted differentiation program in hematopoietic stem and progenitor cells (HSPCs) in diet-induced copper-deficient mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via regulating Mtco1 and Mtco2 (subunits of Complex IV) within HSPCs. Notably, we show that the chemical compound elesclomol, also well-known as a potent cuproptosis agonist, significantly alleviates severe anemia and partially recovers HSPC mitochondrial function in vKO mice via its activity as a copper ionophore, but with no effect on cuproptosis. We thus renamed elesclomol as CupriActivitor1(CuA1), which is a more specific and descriptive term. These findings demonstrate the critical role and mechanism of copper, Slc31a1, and CuA1 in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism. The study sheds light on the molecular basis of HSC fate decisions by copper or CuA1 and opens new avenues for the development of novel therapeutic strategies for copper-related disorders and blood diseases. Given the critical and multifaceted nature of copper, we propose establishing a novel interdisciplinary field termed "Cuprology". This discipline will advance our understanding of copper's roles in physiological and pathological processes.

Keywords:  Copper homeostasis; CupriActivitor1; Cuprology; Cuproptosis; Hematopoiesis; Slc31a1

DOI:  https://doi.org/10.1016/j.scib.2025.05.019
EMBO J. 2025 Jun 05.

A capsular myofibroblastic niche maintains hematopoietic stem cells in the spleen.

Shubham Haribhau Mehatre, Sreelakshmi Sanam, Harsh Agrawal, Amulya V Hejjaji, Akhila S Kumar, Mohammad Tauqeer Alam, Satish Khurana.

  The spleen is a key site for extramedullary hematopoiesis that hosts a rare population of functional hematopoietic stem cells (HSCs). While the microenvironment that supports extramedullary hematopoiesis response has gained interest, a niche for splenic HSCs at steady-state remains undescribed. Here, we have uncovered a red-pulp-specific, myofibroblastic niche that supports murine splenic HSCs within a ≈ 200-μm-wide capsular zone. Detailed spatial-distribution and perturbation analysis showed the importance of myofibroblasts in maintaining HSCs in a quiescent state. Unlike reported for the adult bone marrow, the HSCs in splenic niche were not spatially associated with vascular components. G-CSF-mediated chemokine alteration and 5-FU-induced proliferation resulted in HSCs shifts away from the splenic capsule. Interestingly, upon regaining quiescence, the HSCs re-occupied niches close to capsular myofibroblasts. Proteomic interactome profiles confirmed the relevance of capsular myofibroblasts for splenic HSCs and identified potential niche regulators of HSC maintenance. Together, this study demonstrates a dynamic HSC localization in the spleen and its niche context at homeostasis and under stress. It offers a model to uncover novel regulators crucial for HSC function.

Keywords:  Hematopoietic Niche; Hematopoietic Stem Cells; Myofibroblasts; Proteomics; Spleen

DOI:  https://doi.org/10.1038/s44318-025-00477-2
Mol Ther. 2025 May 30. pii: S1525-0016(25)00403-4. [Epub ahead of print]

Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity.

Rubina Thomas, Julie K Ritchey, John F DiPersio, Miriam Y Kim.

CD117 is a cell surface receptor expressed on hematopoietic stem and progenitor cells (HSPCs) and acute myeloid leukemia (AML), and thus CD117-targeting CAR T cells (CART117) can function as both conditioning for hematopoietic stem cell transplant (HSCT) and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117+ cells in the spleen but not in the BM. Of note, proliferation of BM CD117+ cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by Treg depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.

DOI: https://doi.org/10.1016/j.ymthe.2025.05.033
Exp Hematol. 2025 May 29. pii: S0301-472X(25)00106-7. [Epub ahead of print] 104815

FOXP1 contributes to murine hematopoietic stem cell functionality.

Françoise Levavasseur, Samia Oussous, Alessandro Framarini, Ismael Boussaid, Panhong Gou, Zubaidan Tuerdi, Iman Litchy Boueya, Helyette Hoffner, Marta De Almeida, Morgane Le Gall, Haley Tucker, Stéphane Giraudier, Didier Bouscary, Michaela Fontenay, Diana Passaro, Isabelle Dusanter-Fourt, Evelyne Lauret.

Transcription factor forkhead box P1 (FOXP1) is a key regulator of immune cell functions. We have shown that FOXP1 contributes to the expansion of human hematopoietic stem/progenitor (HSPC) and acute myeloid leukaemia cells. Here, we investigated the role of FOXP1 in early adult mouse hematopoiesis in vivo. We showed that loss of hematopoietic-specific FOXP1 expression leads to attrition of the HSC and multipotent progenitor (MPP)-1 compartment in parallel with enhancement of myeloid-biased MPP3 in adult bone marrow and fetal liver. Transplantation experiments confirmed that FOXP1-deficient bone marrow had an intrinsic reduced HSC compartment. FOXP1-deficient MPP compartments also showed enhanced proliferation with G0 phase reduction. Transcriptome analyses revealed that FOXP1-deficient HSC exhibited reduced stemness and enhanced expression of cell proliferation pathways. Thus, our current results reveal the important contribution of FOXP1 in early murine hematopoiesis through HSC maintenance, limited expansion of all MPP compartments and restriction of early myeloid commitment in vivo.

DOI: https://doi.org/10.1016/j.exphem.2025.104815
Cell Rep Med. 2025 May 30. pii: S2666-3791(25)00230-7. [Epub ahead of print] 102157

Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.

Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco.

  Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, adversely impacting the safety and efficacy of clinical translation. Our study uncovers a durable senescence-like response in genetically engineered HSPCs triggered by p53 and interleukin (IL)-1/nuclear factor κB (NF-κB) activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways mitigates senescence-associated responses, improving the repopulating capacity of edited HSPCs. Importantly, we identify treatment with Anakinra, an IL-1 signaling antagonist, as a promising strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the editing procedure. Overall, our findings present strategies to overcome key hurdles in HDR-based HSPC gene therapies, providing a framework for enhancing their efficacy and safety in clinical applications.

Keywords:  CRISPR-Cas9; DNA damage; gene editing; gene therapy; genome integrity; hematopoietic stem cells; inflammatory programs; p53; senescence; viral vectors

DOI:  https://doi.org/10.1016/j.xcrm.2025.102157
Methods Mol Biol. 2025 Jun 04.

Stem Cell Niche: iPSC-Based Assembloids for Modeling Human Hematopoiesis.

Madeline J Caduc, Marcelo A S de Toledo, Steffen Koschmieder, Simón Méndez-Ferrer.

  The bone marrow (BM) niche is a highly specialized and dynamic microenvironment that tightly regulates hematopoiesis in both health and disease. In this chapter, we present a protocol for generating patient-specific 3D BM-mimicking assembloids, which offer precise control over cellular composition and genetic background. This in vitro platform enables the dissection of mechanisms underlying hematopoietic regulation and BM niche remodeling. We describe, in detail, the stepwise differentiation of induced pluripotent stem cells (iPSCs) into hematopoietic and endothelial lineages, the isolation of human primary mesenchymal stromal cells (MSCs) from femoral heads, and the assembly of BM-mimicking 3D assembloids. Single-cell RNA sequencing of these assembloids identified key myeloid populations and non-hematopoietic lineages such as endothelial cells and various MSC clusters, all crucial for stem cell fate determination and niche maintenance. Furthermore, assembloids harboring the JAK2V617F driver mutation successfully recapitulated key features of myeloproliferative neoplasms, demonstrating the platform's potential for mechanistic studies in human hematopoiesis. This approach provides a powerful tool to model both physiological and neoplastic BM niches, facilitating preclinical research and drug development while potentially reducing reliance on animal models.

Keywords:  Assembloids; Bone marrow niche; Hematopoiesis; Microenvironment; Patient-derived induced pluripotent stem cells

DOI:  https://doi.org/10.1007/7651_2025_629
Elife. 2025 Jun 06. pii: RP96675. [Epub ahead of print]13

Clearance of protein aggregates during cell division.

Shoukang Du, Yuhan Wang, Bowen Chen, Shuangshuang Xie, Kuan Yoow Chan, David C Hay, Ting Gang Chew.

  Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.

Keywords:  ER reorganization; aggregates; cell biology; chaperone; human; mitosis; proteostasis

DOI:  https://doi.org/10.7554/eLife.96675
bioRxiv. 2025 May 22. pii: 2025.05.20.655179. [Epub ahead of print]

AttentionAML: An Attention-based Deep Learning Framework for Accurate Molecular Categorization of Acute Myeloid Leukemia.

Lusheng Li, Joseph D Khoury, Jieqiong Wang, Shibiao Wan.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy defined by aberrant clonal expansion of abnormal myeloid progenitor cells. Characterized by morphological, molecular, and genetic alterations, AML encompasses multiple distinct subtypes that would exhibit subtype-specific responses to treatment and prognosis, underscoring the critical need of accurately identifying AML subtypes for effective clinical management and tailored therapeutic approaches. Traditional wet lab approaches such as immunophenotyping, cytogenetic analysis, morphological analysis, or molecular profiling to identify AML subtypes are labor-intensive, costly, and time-consuming. To address these challenges, we propose AttentionAML , a novel attention-based deep learning framework for accurately categorizing AML subtypes based on transcriptomic profiling only. Benchmarking tests based on 1,661 AML patients suggested that AttentionAML outperformed state-of-the-art methods across all evaluated metrics (accuracy: 0.96, precision: 0.96, recall of 0.96, F1-score: 0.96, and Matthews correlation coefficient: 0.96). Furthermore, we also demonstrated the superiority of AttentionAML over conventional approaches in terms of AML patient clustering visualization and subtype-specific gene marker characterization. We believe AttentionAML will bring remarkable positive impacts on downstream AML risk stratification and personalized treatment design. To enhance its impact, a user-friendly Python package implementing AttentionAML is publicly available at https://github.com/wan-mlab/AttentionAML .

DOI: https://doi.org/10.1101/2025.05.20.655179
bioRxiv. 2025 May 19. pii: 2022.07.22.501030. [Epub ahead of print]

In vivo CRISPR screening identifies SAGA complex members as key regulators of hematopoiesis.

Michael S Haney, Archana Shankar, Leonid Olender, Ian Hsu, Masashi Miyauchi, Róbert Pálovics, Grace A Meaker, Satoshi Kaito, Ola Rizq, Hwei Minn Khoo, Yavor Bozhilov, Kyomi J Igarashi, Joydeep Bhadury, Christy Munson, Paul K Mack, Tze-Kai Tan, Jan Rehwinkel, Atushi Iwama, Tony Wyss-Coray, Hiromitsu Nakauchi, Adam C Wilkinson.

The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for novel regulators of hematopoiesis, we performed genome-wide in vivo hematopoietic stem cell (HSC)-based CRISPR knockout screens for regulators of hematopoiesis. We discovered SAGA complex members, including Tada2b and Taf5l , as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibited hematopoiesis in vivo , led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. Loss of these factors also enhanced the cell outgrowth and the interferon pathway in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression. In summary, this study has identified the SAGA complex as an important regulator of hematopoiesis.

DOI: https://doi.org/10.1101/2022.07.22.501030
Nat Commun. 2025 Jun 03. 16(1): 5152

Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis.

Xiaohui Liu, Marianne Montemurro, Nathalie Vanzo, Michèle Crozatier.

In adult mammals, hematopoietic stem/progenitor cells reside in the bone marrow, in a specialized microenvironment called a "niche", which is composed of different cell types, including nerves. Although it is established that sympathetic nerves regulate hematopoiesis, little is known about the role of neural serotonin in bone marrow. The Drosophila hematopoietic organ, the lymph gland, is aligned along the aorta, which corresponds to the vascular niche. Here, we report that serotonin signaling in the vascular niche regulates the hematopoietic response to an immune challenge. The serotonin receptor 1B expressed in vascular niche cells, together with serotonin produced by neurons regulate the degradation of the extracellular matrix of the lymph gland and prevent its premature dispersal after an immune challenge. Serotonin signaling in aorta cells acts via JAK/STAT pathway activation. Our results provide novel insights into how vascular niche cells integrate neural information to regulate lymph gland immune stress hematopoiesis.

DOI: https://doi.org/10.1038/s41467-025-60493-y
bioRxiv. 2025 May 22. pii: 2025.05.17.654633. [Epub ahead of print]

Targetable BIRC5 dependency in therapy-resistant TP53 mutated acute myeloid leukemia.

Ahmed M Mamdouh, Fang Qi Lim, Yang Mi, Elyse A Olesinski, Cheryl Gek Teng Chan, Shaista Jasdanwala, Xiao Xian Lin, Yichen Wang, Jordan Yong Ming Tan, Karanpreet Singh Bhatia, Valeriia Sapozhnikova, Chuqi Wang, Aarthi Nivasini Mahesh, Daniel Tan En Liang, Nishtha Chitkara, Philipp Mertins, Leah Hogdal, Brandon D Brown, Torsten Haferlach, Camille Lobry, Coleman Lindsley, Alexandre Puissant, Han Kiat Ho, Sanjukta Das, Anthony Letai, Steven M Kornblau, Jan Krönke, Edward Ayoub, Koji Itahana, Michael Andreeff, Shruti Bhatt.

TP53 mutations confer treatment resistance across multiple cancers. Mechanisms of therapy resistance, beyond affecting transactivation of BCL-2 family genes, remain a mystery. Here, we report that TP53 mutated AML, triple negative breast cancer, and colorectal cancer escape therapy-induced apoptosis due to inability to activate caspase-3/7, despite having normal mitochondrial outer membrane permeabilization (MOMP) induction. To identify post-MOMP determinants of therapy resistance in TP53 mutated AML, we applied a multiomics approach - whole-genome CRISPR screen, bulk/single-cell RNAseq, and high-throughput drug screen. BIRC5 , encoding survivin, was selectively upregulated in paired hematopoietic stem/multipotent progenitor cells from TP53 mutant AML patients, with further enrichment after venetoclax-azacitidine (VenAza) relapse. Critically, BIRC5 was also upregulated in 17 of 26 TP53 mutant TCGA cancers. Genetic ablation of BIRC5 resensitized TP53 mutated AML to standard therapy by restoring caspase activation, validating therapeutic relevance. Importantly, targeting IAPs and survivin using clinically relevant inhibitors overcame VenAza resistance of TP53 mutant tumors in vivo , achieving sustained AML suppression. Combination with survivin inhibitors also overcame chemotherapy resistance in TP53 deficient solid cancers. Together, we discovered that wild-type TP53 is required in post-MOMP signaling and that BIRC5 dependency is an effective therapeutic target for poor prognosis, TP53 mutated cancers.

DOI: https://doi.org/10.1101/2025.05.17.654633
Haematologica. 2025 Jun 05.

Comprehensive characterization of human bone marrow microenvironment shows age-related changes.

Mareike Peters, Patric Teodorescu, Sergiu Pasca, Xuan Zhang, Rulin Wang, Srinivasan Yegnasubramanian, Leighton H Grimes, Nathan Salomonis, Lukasz P Gondek, Gabriel Ghiaur.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.287536
Blood Neoplasia. 2025 May;2(2): 100072

Targeting transcription-replication conflicts using G-quadruplexes stabilizers in multiple myeloma.

Laure Dutrieux, Sara Ovejero, Antoine Guillemin, Miss Leriem Zellagui, Elke De Bruyne, Catharina Muylaert, Lien Van Hemelrijck, Yea-Lih Lin, Elle Loughran, Armelle Choquet, Talha Magat, Soumya Bouchouika, Caroline Bret, Guilhem Requirand, Nicolas Robert, Laure Vincent, Guillaume Cartron, Charles Herbaux, Raphaël Rodriguez, Michel Cogné, Eric Rivals, Jean-Christophe Andrau, Alexandre David, Philippe Pasero, Jérôme Moreaux.

Replication stress exerts an important role in fueling genomic instability characterizing multiple myeloma (MM) evolution and is a leading cause of drug resistance. Normal and malignant plasma cells (PCs) are associated with a high transcriptional stress due to the huge production of immunoglobulins. Transcription-replication conflicts (TRCs), arising from collisions between replication and transcription machineries, can promote tumor progression and represent an Achilles' heel to cancer cells. We reported a gene signature related to TRCs management (TRC score), overexpressed in malignant vs normal PCs. High TRC score identified patients with MM with a poor prognosis who could benefit from a TRC-enhancing therapy, in independent cohorts of patients with MM treated with high-dose melphalan chemotherapy or anti-CD38 immunotherapy. Here, we investigated the therapeutic interest of increasing TRCs to target specifically malignant PCs using the G-quadruplex (G4) stabilizer pyridostatin (PDS). PDS exerted significant toxicity in MM cell lines and primary MM cells, inducing DNA damage, cell cycle arrest, and apoptosis. Importantly, primary myeloma cells are significantly more sensitive to PDS treatment than normal bone marrow cells. Moreover, PDS improved the efficacy of MM treatments such as melphalan and histone deacetylase (HDAC) or bromodomain (BRD) inhibitors. Thus, our study shows that G4 stabilizers could be used to specifically target MM cells that exhibit concomitant replication stress and a high level of transcription, through the increase of TRCs. These molecules could be used to increase the efficacy of other treatments including melphalan, HDAC inhibitors, and BRD inhibitors.

DOI: https://doi.org/10.1016/j.bneo.2025.100072
J Biol Chem. 2025 May 30. pii: S0021-9258(25)02170-2. [Epub ahead of print] 110320

The transcription factor HOXA9 induces expression of the chromatin modifier SMYD3 to drive leukemogenesis.

Liping Zhang, Jinqiu Zhong, Luo Yang, Qianyun Ye, Yanli Jin, Chang Liu, Peilong Lai, Hongle Li, Jingxuan Pan, Bei Jin.

  Fusion oncogene MLL-AF9 initiates AML via downstream targets such as HOXA9. Drivers in the complicated settings of advanced AML, however, remain to be incompletely elucidated. Any factors to incur upregulation of the effector HOXA9 predictably aggravate the effect of DOT1L-mediated H3K79 methylation on HOXA9 expression in MLL-AF9-driven AML. In the present study, we identified that SET and MYND domain-containing protein 3 (SMYD3) was overexpressed in AML and predicted a poor prognosis for AML patients. Given that H3K4me3 typically activates the transcription of oncogenes, we hypothesized that SMYD3-catalyzed H3K4me3 may directly increase HOXA9 transcription, offering an additional regulation layer to HOXA9 gene transcription activation in MLL-AF9 AML. We tested this hypothesis and unveiled that SMYD3 is responsible for mediating H3K4me3 enrichment and for independently activating HOXA9 transcription. Transcription factor HOXA9 in turn bound to the promoter region of SMYD3 and enhanced its transcription. The resultant vicious circle of SMYD3-H3K4me3-HOXA9 exacerbated proliferation and blocked differentiation in both AML cell lines and primary cells fractionated from patients with AML. Combinational disruption of this loop and DOT1L inhibition led to enhanced anti-leukemia activity against MLL-AF9 AML in vitro and in vivo. In conclusion, our findings may advocate the current understanding regarding the underlying mechanism and offer SMYD3 as a promising intervention target to override the complicated settings in advanced AML.

Keywords:  AML; HOXA9; MLL-AF9; SMYD3; differentiation; positive feedback loop; transcription activation

DOI:  https://doi.org/10.1016/j.jbc.2025.110320
Nat Commun. 2025 Jun 02. 16(1): 5129

A non-genotoxic stem cell therapy boosts lymphopoiesis and averts age-related blood diseases in mice.

Anna Konturek-Ciesla, Qinyu Zhang, Shabnam Kharazi, David Bryder.

Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we employ a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion. While aging presents a significant barrier to effective HSC engraftment, optimizing HSC doses and non-genotoxic targeting methods greatly enhance the long-term multilineage activity of the transplanted cells. We demonstrate that young HSCs, once effectively engrafted in aged hosts, improve hematopoietic output and ameliorate age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigates disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-genotoxic HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a prophylactic tool to delay or even prevent their onset in elderly patients.

DOI: https://doi.org/10.1038/s41467-025-60464-3
bioRxiv. 2025 May 14. pii: 2025.05.13.651470. [Epub ahead of print]

Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.

Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.

Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to synthesize serine, responded to SG restriction in vivo , and were rescued by restoring PSAT1. We also found that AML with an SF3B1 K700E mutation showed additional dependence on the SSP enzyme PHGDH, that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.

DOI: https://doi.org/10.1101/2025.05.13.651470
Autophagy Rep. 2025 ;4(1): 2507266

Active protein quality control in quiescence: involvement of proteasomes, autophagy, and nucleus-vacuole junctions.

Mihaela Pravica, Dina Franić, Mirta Boban.

  Quiescence is a conserved, reversible state of proliferative arrest, characterized by changes in cell physiology and metabolism. Many cells spend a considerable part of their lifetime in quiescence, including adult stem cells or microorganisms facing unfavorable environmental conditions. Cells can remain quiescent for long periods of time while retaining their viability and reproductive capacity, indicating a need to maintain protein homeostasis. Given the changes in intracellular organization, it has been unclear how protein quality control (PQC) functions in quiescent cells. In our recent study, we examined model misfolded proteins expressed in glucose-depleted quiescent yeast cells and found that quiescent cells maintain an active PQC that relies primarily on selective protein degradation, requiring the ubiquitin-proteasome system, intact nucleus-vacuole junctions and autophagy. Our results highlight the relevance of mitigating misfolded proteins in quiescence.

Keywords:  Nucleus-vacuole junction; Vac8; proteasome storage granule; protein aggregate; protein quality control; quiescence; yeast

DOI:  https://doi.org/10.1080/27694127.2025.2507266
bioRxiv. 2025 May 24. pii: 2025.05.20.655224. [Epub ahead of print]

Cheminformatic identification of small molecules targeting acute myeloid leukemia.

Megan R Daneman, Bernadetta Meika, Elissa Tjahjono, Alexey V Revtovich, Leonid A Stolbov, Scott R Gilbertson, Vladimir V Poroikov, Natalia V Kirienko.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that has poor prognosis and high relapse rates with cytotoxic chemotherapeutics. Previously, we identified modulators of mitochondrial function, PS127-family compounds, that were cytotoxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition (T/GRi). Here, we uncovered a third critical predicted function: autophagic induction. A cheminformatics screening of ∼4.2 million compounds for molecules with high probability of these three functions yielded 93 hits, 81 of which were closely related to PS127-family molecules. In silico hits selected for validation selectively killed AML cells, activated apoptosis, required functional autophagy, and interfered with glutathione metabolism, confirming predicted functions. This increased pools of cytosolic and mitochondrial ROS and decreased oxygen consumption and ATP synthesis. Differential scanning fluorimetry implicated glutathione reductase as a direct target of these molecules. Structurally-unrelated compounds from different clusters caused the same phenotype, validating our structure-blind screening approach. Furthermore, strong synergy between these compounds and the AML treatment midostaurin underscores their therapeutic potential.

DOI: https://doi.org/10.1101/2025.05.20.655224
bioRxiv. 2025 May 24. pii: 2025.05.22.655396. [Epub ahead of print]

Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.

Mark J Althoff, Mohd Minhajuddin, Brett M Stevens, Austin E Gillen, Stephanie Gipson, Sweta B Patel, Ian T Shelton, Regan Miller, Ana Vujovic, Anna Krug, Tracy Young, William M Showers, Monika Dzieciatkowska, Daniel Stephenson, Anit Tyagi, Jana M Ellegast, Tristen Wright, Kimberly Stegmaier, Joseph T Opferman, Angelo D'Alessandro, Clayton A Smith, Craig T Jordan.

While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 ( ACSL1 ), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1 , thereby promoting ven/aza-resistance in AML.

DOI: https://doi.org/10.1101/2025.05.22.655396
Nat Rev Drug Discov. 2025 Jun 02.

Blocking a cell surface protein beats AML.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00095-x
Nat Commun. 2025 Jun 04. 16(1): 5179

An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.

Yicheng Wang, Pengfei Song, Heqing Zhou, Pengwei Wang, Yan Li, Zhiyong Shao, Lu Wang, Yan You, Zuhai Lei, Jinhua Yu, Cong Li.

Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41467-025-60315-1
Blood Neoplasia. 2024 Sep;1(3): 100017

Real-world outcomes of newly diagnosed AML treated with venetoclax and azacitidine or low-dose cytarabine in the UK NHS.

Jad Othman, Ho Pui Jeff Lam, Sarah Leong, Faisal Basheer, Islam Abdallah, Kathryn Fleming, Priyanka Mehta, Heba Yassin, John Laurie, Michael Austin, Paolo Gallipoli, Tom Taylor, Mike Dennis, Johnathon Elliot, Georgina Clarke, Raymond Dang, Jennifer Vidler, Pramila Krishnamurthy, Anne-Louise Latif, Pallavi Kalkur, Maryam Shahidianakbar, Victoria Campbell, Deepak Mannari, Emily Sutherland, Thishakya Wickramaratne, Angela Collins, Rui Zhao, Herng Mak, Edward Belsham, Shabnam Banerjee, Jamila Bashir, Srinivas Pillai, Richard Whitmill, Sofia Galli, Mariam Amer, Vidhya Murthy, Duncan Murray, Farooq Wandroo, Francesca Hogan, Francesca Crolla, Nicole Fowler, Anjum Khan, Jenny O'Nions, Richard Dillon.

Venetoclax with azacitidine is the standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; however, uncertainties remain regarding the treatment schedule, accurate prognostication, and outcomes for patients treated outside clinical trials. The option of venetoclax with low-dose cytarabine (LDAC) is also available; however, it is not clear for which patients it may be a useful alternative. Here, we report a large real-world cohort of 654 patients treated in 53 UK hospitals with either venetoclax and azacitidine (n = 587) or LDAC (n = 67). The median age was 73 years, and 59% had de novo AML. Most patients received 100 mg of venetoclax with an azole antifungal. In cycle 1, patients spent a median of 14 days in the hospital, and 85% required red cell transfusion, 59% platelet transfusion, and 63% required IV antibiotics. Supportive care requirements significantly reduced after the first cycle. Patients receiving venetoclax-azacitidine had a complete remission (CR)/CR with incomplete hematological recovery rate of 67%, day 30 and day 60 mortality of 5% and 8%, respectively, and median overall survival of 13.6 months. Mutations in NPM1, RUNX1, STAG2, and IDH2 were associated with improved survival, whereas age, secondary and therapy-related AML, +8, MECOM rearrangements, complex karyotype, ASXL1, and KIT mutations were associated with poorer survival. Prognostic systems derived specifically for patients treated with venetoclax-azacitidine performed better than the European LeukemiaNet and Medical Research Council classifications; however, improved risk classifications are still required. In the 149 patients with NPM1 mutated AML, outcomes were similar for those treated with venetoclax-azacitidine and venetoclax-LDAC.

DOI: https://doi.org/10.1016/j.bneo.2024.100017
Blood Neoplasia. 2025 May;2(2): 100083

Multiplex gene editing models of del(7q) reveal combined CUX1 and EZH2 loss drives clonal expansion and drug resistance.

Matthew R M Jotte, Angela Stoddart, Tanner C Martinez, Raven Moten, Yuqing Xue, Molly K Imgruet, Hunter Blaylock, Henna S Nam, Bonnie Hu, Jermaine Austin, Ningfei An, Saira Khan, Sandeep K Gurbuxani, Megan E McNerney.

Loss of all or part of chromosome 7 [-7/del(7q)] is recurrent in myeloid neoplasms and associated with a poor response to chemotherapy. Chromosome 7-encoded genes driving drug resistance and the consequences of combinatorial 7q tumor suppressor gene loss have remained unclear, the latter question largely because of the challenges of modeling aneuploidy. Here, we use in silico data mining to uncover 7q genes involved in chemotherapy resistance. We establish murine models of del(7q) clonal hematopoiesis and drug resistance with multiplex CRISPR-Cas9 (CRISPR-associated protein 9)-mediated inactivation of 4 genes, Cux1, Ezh2, Kmt2c, and Kmt2e. Postgenotoxic exposure, combined deficiency of Cux1 and Ezh2 preferentially promotes clonal myeloid expansion in vivo, with compounding defects in DNA damage recognition and repair. Human acute myeloid leukemia cell lines similarly illustrate central roles for CUX1 and EZH2 loss in survival and DNA damage resolution after chemotherapy exposure. Transcriptome analysis reveals combined Cux1 and Ezh2 loss recapitulates gene signatures of -7 patients and defective DNA damage response pathways, to a greater extent than single gene loss. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to leukemogenesis and drug resistance characteristic of these adverse-risk neoplasms. These data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple gene drives pathogenesis. Furthermore, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer.

DOI: https://doi.org/10.1016/j.bneo.2025.100083
FASEB J. 2025 Jun 15. 39(11): e70665

Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.

Huizhen Lin, Jingwen Qi, Siwei Lin, Mengnan Lin, Zijie Chen, Yunhui Guo, Xin Zhang, Qi-Long Wang, Ting Cai, Wei Yang, Xiaojun Zheng.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a manifestation of systemic metabolic disease defined by abnormal lipid metabolism and causes liver disease. Inflammation driven by immune cells has been linked to liver damage, fibrosis, and the progression of MASH. Here, single-cell transcriptome analysis disclosed the increasing hepatic infiltration of CD8+ T cells in a murine methionine- and choline-deficient (MCD) diet-induced MASH model. Simvastatin alleviated the progression of MCD-diet-induced MASH, accompanied by the decreased infiltration of T cells. Depletion of CD8+ T cells also improved MASH progression. It is widely recognized that cholesterol plays an indispensable role in tuning the activation and function of CD8+ T cells. We found that specific inhibition of cholesterol synthesis in T cells significantly reduced MCD-induced hepatic steatosis, damage, inflammation, and concurrently lowered the accumulation of T cells and macrophages in the liver. Mechanistic studies revealed that MCD-induced hepatic oxidative stress was reduced by inhibiting T-cell cholesterol metabolism. Simvastatin ameliorated MASH in mice, at least in part through inhibiting the infiltration and effector function of CD8+ T cells. Collectively, our findings provide compelling evidence that pharmacological modulation of T-cell cholesterol metabolism may represent a promising therapeutic approach in the treatment of MASH.

Keywords:  T cells; cholesterol; metabolic dysfunction‐associated steatohepatitis; oxidative stress; simvastatin

DOI:  https://doi.org/10.1096/fj.202500115R
Cell Death Discov. 2025 Jun 04. 11(1): 266

ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation.

Yingping Li, Fenna Zhang, Fumin Hu, Rui Tong, Yueqi Wen, Guokai Fu, Xueli Bian.

Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.

DOI: https://doi.org/10.1038/s41420-025-02544-3