bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–12–07
twelve papers selected by
William Grey, University of York
  1. Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
  2. Human TET2-mutant clonal hematopoiesis expansion is driven by distinct inflammatory signaling responses in stem cells versus myeloid progeny.
  3. In vivo gene editing of human hematopoietic stem and progenitor cells using envelope-engineered virus-like particles.
  4. Ace2 safeguards embryonic hematopoietic stem and progenitor cell production by restraining Nlrp3-mediated pyroptosis.
  5. Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy.
  6. FLT3-directed BiTE Molecules versus CAR T Cells in AML: Co-stimulatory Signals Mitigate T-Cell Exhaustion.
  7. Studying clonal heterogeneity of acute myeloid leukemia under nutrient and chemotherapy stress.
  8. THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.
  9. Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
  10. Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.
  11. Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.
  12. Targeting DESI2 as a Novel Therapeutic Strategy for JAK2-Mutant Leukemias.
  1. Sci Adv. 2025 Dec 05. 11(49): eaea7451
    Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
    Longfei Gao, Desmond Dickson, Huijuan Feng, Chaolin Zhang, Lei Ding.
      Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
    DOI:  https://doi.org/10.1126/sciadv.aea7451
  2. Blood Cancer Discov. 2025 Dec 03.
    Human TET2-mutant clonal hematopoiesis expansion is driven by distinct inflammatory signaling responses in stem cells versus myeloid progeny.
    Hector Huerga Encabo, Giuseppe D'Agostino, Katherine Sturgess, Alice E Lord, Eric D Jong, Alessandra Ferrelli, Aneesh Sharma, Syed A Mian, Khadidja Habel, Miriam Llorian-Sopena, Amirtha Priya Ramesh, Fatihah Mohamad Nor, Helene Foissner, Manuel Garcia-Albornoz, Lynette Graver, Despoina Papazoglou, Steven Ngo, Fernando Anjos-Afonso, Linda Ariza-McNaughton, Gabriella Ficz, Dominique Bonnet.
      Clonal hematopoiesis (CH) increases with age and is associated with severe outcome in the course of infections or tumor development. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. Using human cells, we unravel a cell-specific and opposite impact of TET2 mutations on hematopoietic stem and progenitor cells (HSPC) compared to their myeloid progeny. Multi-omic analyses reveal that TET2-mutant HSPCs exhibit intrinsic epigenetic silencing of AP-1 transcription factors and a blunted transcriptional adaptation to systemic inflammation. Conversely, monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to exacerbated inflammation. Together, these findings reconcile how TET2-mutant CH can simultaneously promote increased stemness within the HSPC compartment and heightened inflammation through its myeloid progeny, providing mechanistic insight into how TET2-CH expands under inflammatory stress.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0070
  3. Nat Biotechnol. 2025 Dec 05.
    In vivo gene editing of human hematopoietic stem and progenitor cells using envelope-engineered virus-like particles.
    Vladimir V Botchkarev, Sean Harrington, Matteo Stoppato, Alexander Justen, Casey Kimber, Anjali Kapuria, Keylie M Gibson, Chi-Shuen Chu, Yuanxin Xu, Kelsey Haugh, Ramya Ankala, Nathan Kipniss, Andre DeGroot, Emerson Moore, Rowena de Jesus, Funmi Adewale, Kathy Daniels, Samantha Crocker, Anna Liang, Shannon Joyce, Nicole Roberto, Pamela Angel, Derek Smith, Athena Wong, Nick Adler, Valeria Berlfein, Shirisha Amatya, Patricia Cruite, Shariq Usmani, Albert Ruzo, Benjamin Ferland, Sundeep Chandra, Edward J Rebar, Jagesh V Shah, Kyle Trudeau, Luca Biasco.
      Engineered virus-like particles (VLPs) are a promising technology for in vivo gene editing of human hematopoietic stem and progenitor cells (HSPCs). Here we design and test two different VLP envelopes for human HSPC editing in vitro and in vivo. The first is an optimized version of the baboon envelope BaEVTR, which efficiently transduces human HSPCs in vitro. We show that the optimized BaEVTR VLP enables in vivo editing of β2 microglobulin in long-term human HSPCs (31% at 8 weeks after dosing) and editing of two hemoglobinopathy-relevant loci, BCL11A and HBG1/2 (26% and 7.5%, respectively, at 5 days after dosing), inducing fetal hemoglobin. Our second VLP design uses a CD133-targeted envelope designed to reduce the transduction of mature blood cells and achieves higher in vivo specificity for HSPCs compared to the optimized BaEVTR VLP. As avoiding delivery in filter organs such as the liver would enhance efficiency and safety, we also demonstrate that both VLPs avoid human hepatocytes in a humanized liver model.
    DOI:  https://doi.org/10.1038/s41587-025-02915-2
  4. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2515641122
    Ace2 safeguards embryonic hematopoietic stem and progenitor cell production by restraining Nlrp3-mediated pyroptosis.
    Jun Xia, Lingxue Shen, Yining Liu, Lu Wang, Feng Liu.
      During vertebrate embryogenesis, hematopoietic stem and progenitor cells (HSPCs) originate from hemogenic endothelium (HE) in the dorsal aorta through endothelial-to-hematopoietic transition (EHT). While basal inflammation is essential for this process, excessive immune activation disrupts HSPC emergence. Here, we identify angiotensin-converting enzyme 2 (Ace2), a key component of renin-angiotensin system, as a crucial anti-inflammatory regulator of embryonic hematopoiesis in zebrafish and mice. Loss of Ace2 impairs HE specification and reduces nascent HSPC production. Mechanistically, transcriptomic profiling reveals that ace2 deficiency leads to aberrant activation of NLR family pyrin domain containing 3 (Nlrp3) signaling and pyroptosis in vascular endothelial cells. Importantly, pharmacological inhibition of Nlrp3 or Caspase-1 restores HSPC emergence upon ace2 deficiency, consistent with treatment with exogenous angiotensin-(1-7) [Ang-(1-7)], a downstream product of Ace2 enzymatic activity. Moreover, Ace2 knockdown in mouse embryos phenocopies the defects in zebrafish, demonstrating evolutionary conservation of ACE2 in developmental hematopoiesis in mammals. Together, our findings uncover an essential role for ACE2 in maintaining a permissive inflammatory environment for HSPC development and suggest therapeutic potential for targeting the ACE2/Ang-(1-7)/Nlrp3-pyroptosis axis in inflammatory hematopoietic disorders.
    Keywords:  Ace2; Nlrp3 signaling; hematopoietic stem and progenitor cells; pyroptosis; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2515641122
  5. Nat Commun. 2025 Dec 01. 16(1): 10800
    Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy.
    Mingming Zhu, Haoxiang Yang, Kailong Qiu, Beibei Huang, Tingting Liang, Yan Wang, Huan Li, Mingming Wu, Xinru Liu, Na Zhao, Xian Song, Xuxu Zhao, Mengqing Gao, Yue Zhao, Xiangting He, Rui Zhao, Lili Qian, Qinhua Liu, Changcheng Zheng, Xiaoyu Zhu, Hongyuan Jiang, Fang Ni.
      Acute myeloid leukemia (AML) is primarily driven by leukemic stem cells (LSCs), the main cause of relapse and therapy resistance. Here, we discover that LSCs are predominantly small and mechanically soft. These mechanical properties enable their selective isolation using microfluidic chips. Single-cell RNA-sequencing of primary human AML bone marrow identifies enrichment of LSCs within the FSClow ALDH1A1+ subpopulation, which exhibits long-term stemness in functional assays. Notably, inhibiting ALDH1A1 in these cells promotes F-actin polymerization and increases cellular stiffness, reducing their stemness while enhancing their susceptibility to natural killer (NK) cell-mediated cytotoxicity. In AML patient-derived xenograft models, the combination of ALDH1A1 inhibition with NK cell therapy markedly suppresses leukemia progression. These findings suggest that targeting the mechanical properties of LSC offers a promising strategy to overcome AML treatment resistance, providing insights into stem cell mechanobiology and paving the way for combining targeted therapies with immunotherapy to improve clinical outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-65842-5
  6. Blood Adv. 2025 Dec 01. pii: bloodadvances.2025018168. [Epub ahead of print]
    FLT3-directed BiTE Molecules versus CAR T Cells in AML: Co-stimulatory Signals Mitigate T-Cell Exhaustion.
    Lisa Rohrbacher, Daniel Nixdorf, Helena Stadler, Bettina Brauchle, Florian Märkl, Adrian Gottschlich, Gordon Victor Hoffmann, Nora Philipp, Gerulf Hänel, Martin Edwin Kirmaier, Anetta Marcinek, Maryam Kazerani, Daniel Richter, Giulia Magno, Rebecca L Goldstein, Sebastian Theurich, Tobias Straub, Sebastian Kobold, Tara Arvedson, Veit L Bücklein, Marion Subklewe.
      T-cell-based immunotherapies have revolutionized treatment paradigms in B-cell malignancies, yet their translation to acute myeloid leukemia (AML) has been hindered by a scarcity of tumor-restricted antigens and the risk of on-target off-leukemia toxicity. FLT3 has emerged as a promising therapeutic target with limited expression in healthy hematopoietic tissues. Here, we performed a head-to-head preclinical comparison of a FLT3-directed bispecific T-cell engager (BiTE) molecule and second-generation FLT3-specific chimeric antigen receptor (CAR) T cells. Both approaches induced potent cytotoxicity against AML cell lines and primary patient-derived cells but spared healthy hematopoietic stem and progenitor cells in vitro. Despite similar short-term efficacy, prolonged antigen exposure demonstrated progressive functional decline and metabolic exhaustion; however, CAR T cells maintained cytotoxic capacity and proliferative potential over time. In AML xenograft models, CAR T cells achieved superior tumor control, prolonged survival, and greater T-cell infiltration than BiTE molecule-treated counterparts. Transcriptomic profiling of T cells recovered from bone marrow further revealed a distinct exhaustion-associated gene signature in samples from mice that had been treated with the FLT3 BiTE molecule. Importantly, provision of CD86-mediated co-stimulation enhanced antitumor activity of BiTE-redirected T cells in vitro and in vivo. These findings establish FLT3 as a viable and selective immunotherapeutic target in AML and underscore the functional and transcriptional differences between BiTE molecule-redirected T cells and CAR T cells. Moreover, they reveal a critical role for costimulatory signaling in sustaining the efficacy of T-cell-based therapies in vivo, offering a rationale for improving T-cell redirection strategies in myeloid malignancies.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018168
  7. Blood Adv. 2025 Dec 06. pii: bloodadvances.2025016618. [Epub ahead of print]
    Studying clonal heterogeneity of acute myeloid leukemia under nutrient and chemotherapy stress.
    Christina Mayerhofer, Eve Crompton, Ernst Mayerhofer, Trine A Kristiansen, Tsuyoshi Fukushima, Samuel Keyes, Azeem Sharda, Dan Li, Carmen Da Silva, Deumaya Shrestha, Anna Kiem, Tobias Feuchtinger, David T Scadden, Peter Grant Miller.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025016618
  8. Nat Commun. 2025 Dec 01.
    THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.
    Dan Wang, Zhixiang Wu, Siyang Liu, Jing He, Haixia Zhang, Pan Chen, Minghua Yang.
      Induction of ferroptosis is a potential strategy to eliminate chemotherapy-resistant acute myeloid leukemia (AML) cells. Here, we investigate the role and mechanism of thyroid hormone receptor-associated protein 3 (THRAP3) in ferroptosis of AML cells. We show that high expression of THRAP3 is correlated with a poor prognosis in AML patients. THRAP3 knockdown suppresses AML cell proliferation, and delays orthotopic and subcutaneous tumor growth in male mice; however, THRAP3 overexpression exerts the opposite roles. THRAP3 overexpression promotes resistance of AML cells to RSL3/erastin-induced ferroptosis via inhibiting iron accumulation and promoting GSH synthesis. Mechanistically, THRAP3 recruits SLU7 homolog, splicing factor (SLU7) to facilitate GIT ArfGAP 2 (GIT2) Exon14 skipping. Inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance in vitro and in vivo. Altogether, THRAP3 contributes to ferroptosis resistance of AML cells via interaction with SLU7 to trigger GIT2 Exon14 skipping, which suggests THRAP3 to be a therapeutic target for AML.
    DOI:  https://doi.org/10.1038/s41467-025-66931-1
  9. Nat Metab. 2025 Dec 05.
    Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
    Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.
      Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.
    DOI:  https://doi.org/10.1038/s42255-025-01410-x
  10. Blood Adv. 2025 Dec 01. pii: bloodadvances.2025017838. [Epub ahead of print]
    Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.
    Jason David Murray, Teresa K Einhaus, Stefan Radtke, Katharine J Bar, Christopher William Peterson, Hans-Peter Kiem.
      Hematopoietic stem cell (HSC) gene therapies provide lifelong benefit in numerous hematological diseases and disorders, but safety and toxicity remain a critical barrier for routine application. In the setting of immunodeficiency syndromes and infectious diseases such as human immunodeficiency virus (HIV) infection, conditioning regimens may exacerbate immune dysfunction, blunting or impairing overall efficacy. Here, we conduct a head-to-head comparison of two novel antibody drug conjugates (ADC) with a pyrrolobenzodiazepine (PDB) payload for autologous transplantation in rhesus macaques: ADCs targeting either CD117 or CD45 and benchmarked against the clinical standard busulfan. We quantified extent of myeloablation and immunosuppression, time to hematopoietic recovery, long-term engraftment of CCR5 CRISPR-edited autologous HSC, and resistance to infection when challenged with increasing concentrations of an HIV-like virus. Both ADCs enabled engraftment of CRISPR-edited HSCs, although with lower levels of long-term editing compared to busulfan. We observed myeloablation with similar times to hematopoietic recovery and preserved lymphocyte counts with all three conditioning regimens, but neither ADC conditioning nor busulfan enabled sufficient CCR5 editing for viral immunity. While these results only apply to the specific ADC conditioning protocols tested here, they are a step towards developing targeted strategies to engraft cells with therapeutic edits and highlight the need for further refinement of antibody-based selection.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017838
  11. Blood Adv. 2025 Dec 06. pii: bloodadvances.2025018178. [Epub ahead of print]
    Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure.
    Kuo-Kai Chin, Brian J Ball, Yasmin Abaza, Jessica K Altman, Rahul K Thakur, Moiez Ali, Andriy Derkach, Mark B Geyer, Aaron D Goldberg, Tamanna Haque, Meghan C Thompson, Jae H Park, Martin S Tallman, Sheng F Cai, Eunice S Wang, Ibrahim Aldoss, Eytan M Stein.
      Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 U.S. centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation. After MENINi failure, 40% of patients (n=34) received supportive care. Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9). The CR/CRi rate for non-trial therapies was 19% (n=7); ORR was 32% (n=12). All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%). No FLT3-mutant patients responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival (mOS) from start of next therapy was 4.4 months; patients who achieved CR/CRi had mOS of 15.4 vs 3.4 months for non-responders (p=0.048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018178
  12. Adv Sci (Weinh). 2025 Dec 03. e15127
    Targeting DESI2 as a Novel Therapeutic Strategy for JAK2-Mutant Leukemias.
    Husheng Mei, Wuqiang Wen, Wenjun Zhang, Shujing Zhang, Ting Sun, Guiming Li, Jing Zhang, Shuang Qi, Jie Zhou, Bing Li, Yunshuo Zhao, Xiaotong Chen, Bowen Li, Yiying Xue, Wang Lu, Yanli Sun, Jingyao Wang, Hengyue Shan, Shengzhe Zhang, Yushan Huang, Yisa Chen, Wenchao Wang, Qingsong Liu, Wenchao Lu, Li Tan, Yi Ding, Jianfei Fu, Jun Long, Lei Zhang, Baobing Zhao, Aibin Liang, Baishan Jiang, Jing Yang.
      The JAK2-V617F mutation is the most common genetic alteration in myeloproliferative neoplasms (MPN), which can progress to secondary acute myeloid leukemia (sAML), a chemotherapy-resistant disease with limited treatment options and a poor prognosis. Although the JAK1/2 inhibitor Ruxolitinib is clinically approved, its efficacy is limited by toxicity to normal cells and the development of drug resistance. Here, the deSUMOylase DESI2 is identified as a novel component of the JAK2-V617F complex by mass spectrometry-based proteomics. Mechanistically, DESI2 selectively binds to and stabilizes JAK2-V617F by mediating its deSUMOylation and deubiquitination at lysine 962 (K962). Importantly, DESI2 protein is specifically and highly expressed in JAK2-mutant-driven cell lines and MPN primary clinical samples, suggesting its potential role in JAK2-V617F regulation and disease progression. Genetic depletion of DESI2 suppresses both JAK2 mutant cell growth and MPN disease onset in vitro and in vivo. Moreover, through a compound screen, followed by chemical proteomics and compound optimization, WWQ-03-012 is discovered, which selectively degrades mutant JAK2, induces primary leukemia cells death, and inhibits MPN progression through targeting DESI2 enzymatic activity in vitro and in vivo. These studies provide a novel therapeutic strategy against mutated JAK2 signaling in MPN and sAML.
    Keywords:  DESI2; JAK2‐V617F mutation; MPN; degrader; drug resistance
    DOI:  https://doi.org/10.1002/advs.202515127
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