bims-scepro 2026-02-08 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2026–02–08
25 papers selected by
William Grey, University of York

Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system.
A 3D "nichoid" boost for gene-engineered blood stem cells.
DHX9 sustains hematopoietic stem cell function in cooperation with H3 acetylation.
A single cell atlas defines perinatal factors that drive murine bone marrow development.
Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression.
Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.
PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade.
Mutant ASXL1 Drives Transcriptional Activation and Repression in Human Hematopoiesis.
BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
HSCs/MPPs as cells of origin with altered differentiation hierarchy impairing immunomicroenvironment in PML::RARA and CBFα/β fusion AML.
Simultaneous NOD1 and NOD2 Deletion in Hematopoietic Stem and Progenitor cells Promotes Long-Term Donor Chimerism.
TET2 and TP53 Mutations Cooperatively Modulate the Response to Inflammation to Promote Leukemic Transformation.
Proteasome Subunit PSMD1 is a Key Therapeutic Target in Multiple Myeloma.
Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
High-throughput proteomic profiling to evaluate differentiation syndrome with menin inhibition.
Proteostasis of organelles in aging and disease.
Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.
A multivalent adaptor mechanism drives the nuclear import of proteasomes.
Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models.
Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.
Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.
Functional Equivalence of Gamma- and X-Ray Irradiation for Long-Term Peripheral Blood Chimerism and AML Transplant Outcomes in Mice.
Targeting Ikaros and Aiolos: Next-Generation Cereblon E3 Ligase Modulators in MM.
Pediatric acute myeloid leukemia tumor composition predicts patient outcomes at diagnosis and reveals mechanisms of resistance to chemotherapy.
Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.

Haematologica. 2026 Feb 05.

Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system.

Julian Niemann, Tanja Schuster, Vadim Sakk, Karin Soller, Andreas Brown, Sebastian Wiese, Karina Eiwen, Markus Hoenicka, Andreas Liebold, Moritz Oltmanns, Heiko Reichel, Medhanie A Mulaw, Hartmut Geiger.

Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitinconjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging. Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired Tcell development and reduced HSC function. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

DOI: https://doi.org/10.3324/haematol.2025.288847
Cell Stem Cell. 2026 Feb 05. pii: S1934-5909(26)00027-5. [Epub ahead of print]33(2): 167-169

A 3D "nichoid" boost for gene-engineered blood stem cells.

Giulia Schiroli, Pietro Genovese.

Midena et al.1 employ a nanoengineered 3D "nichoid" substrate that mechanically supports CD34+ hematopoietic stem and progenitor cells (HSPCs) during ex vivo manipulation, reducing culture-associated stress and improving engraftment and polyclonal output after gene editing or lentiviral gene addition. The work spotlights mechanobiology as a manufacturing lever for improving HSPC gene therapies.

DOI: https://doi.org/10.1016/j.stem.2026.01.004
Stem Cell Reports. 2026 Feb 05. pii: S2213-6711(26)00005-6. [Epub ahead of print] 102794

DHX9 sustains hematopoietic stem cell function in cooperation with H3 acetylation.

Minhui Shi, Mengqing Gao, Huixin Luo, Chong Wang, Xueyang Hu, Yacen Xiong, Yan Chen, Xingxing Ren, Shu Zhu, Huaiping Zhu.

  Hematopoietic stem cells (HSCs) self-renew to sustain stem cell pools and differentiate into all types of blood cells, whose properties are tightly regulated by epigenetic and transcriptional networks. Here, we identified DHX9 as a critical regulator of HSC maintenance. Dhx9 deletion caused bone marrow failure and impaired hematopoietic reconstitution in murine primary and secondary transplantation recipients due to loss of HSCs and defective self-renewal capacity. Further investigations revealed that Dhx9 deficiency led to aberrant cell cycle entry, increased apoptosis, and elevated ROS, which compromise HSC function. Mechanistically, DHX9 interacts with CBP/p300 acetyltransferase and maintains H3 acetylation at hematopoietic gene promoters to facilitate transcription activation. Inhibition of CBP/p300 disrupted their expression, whereas the enhancement of H3K27ac levels partially rescued hematopoietic defects caused by Dhx9 deficiency in both mouse models and human CD34+ cells. This study highlights DHX9 as a crucial factor linking epigenetic modifications with transcriptional programs in HSC biology.

Keywords:  DHX9; gene transcription; hematopoietic stem cells; histone acetylation

DOI:  https://doi.org/10.1016/j.stemcr.2026.102794
bioRxiv. 2026 Jan 23. pii: 2026.01.21.700817. [Epub ahead of print]

A single cell atlas defines perinatal factors that drive murine bone marrow development.

Brian M Dulmovits, Carson Shalaby, Fangfang Song, James Garifallou, Joshua Bertels, Fanxin Long, Christopher S Thom.

Processes that direct initial colonization and maturation of the bone marrow remain elusive, despite their importance to lifelong hematopoiesis. Bone marrow mesenchymal and stromal cell (BMSC) maturation must establish supportive hematopoietic niches prior to the recruitment and colonization of hematopoietic stem cells (HSCs). Here, we define the identity of murine BMSC progenitors and temporal nature of marrow colonization through a single cell atlas spanning late gestation through 18 months of age. We define progenitor cells and developmental trajectories for Cxcl12-abundant reticular (CAR) cells and osteoblasts within the marrow, including the emergence of direct and secreted signaling modalities that impact HSC quiescence and regenerative capacity. We further identify temporal changes in Early B Cell Factor (Ebf) 1-3 transcription factor expression and activity that correlate with niche establishment. These transcriptional activities relate to change to changes in systemic physiology, including metabolic, inflammatory, and hypoxic signaling, that direct CAR cell emergence after birth in mice. These findings provide unprecedented resolution to the colonization and maturation of the murine bone marrow environment.

DOI: https://doi.org/10.64898/2026.01.21.700817
Nat Commun. 2026 Feb 05.

Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression.

Vincent Cuminetti, Emeline Boet, Marcel Heugel, Joanna Konieczny, Aurora Bernal, Manuel J Gomez, Franco Grimolizzi, Nuria Vilaplana-Lopera, Marc Ferré, Alicia Villatoro, Deo P Pandey, Carlos Torroja, Hagar Taman, Ruth H Paulssen, Thomas Vogl, Caroline A Heckman, Anders Vik, Giovanna Giovinazzo, Nick van Gastel, Paloma García, Fátima Sánchez-Cabo, Jean-Emmanuel Sarry, Lorena Arranz.

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato+ HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

DOI: https://doi.org/10.1038/s41467-026-68906-2
Nat Commun. 2026 Feb 05.

Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.

Zhenlong Li, Rui Ma, Hejun Tang, Ningyuan Liu, Jianying Zhang, Guido Marcucci, Michael A Caligiuri, Jianhua Yu.

Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34+CD38+ to CD34-CD38+ cells and blocks the differentiation of LSCs (CD34+CD38-) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34-CD38+ to CD34-CD38- cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin-CD127+CD161-CRTH2-CD117- (CD161- ILC1s) that can be generated from umbilical cord blood CD34+ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.

DOI: https://doi.org/10.1038/s41467-026-68582-2
bioRxiv. 2026 Jan 23. pii: 2026.01.20.700677. [Epub ahead of print]

PU.1 inhibition sensitizes stem-monocytic AML to BCL2 blockade.

William M Yashar, Itallia V Pacentine, Akram Taherinasab, Thai Nguyen, Samantha Worme, Mitsuhiro Tsuchiya, Theresa Lusardi, Chelsea Hutchinson, Thomas L Fillmore, Camilo Posso, Sara Jc Gosline, Paul D Piehowski, Galip Gurkan Yardimci, Andrew C Adey, Julia E Maxson, Theodore P Braun.

Acute myeloid leukemia (AML) exhibits substantial transcriptional heterogeneity across differentiation states that influences therapeutic response to BCL2 inhibition with venetoclax. While hematopoietic stem cell (HSC)-like AMLs show high sensitivity to venetoclax and monocytic-like AMLs demonstrate resistance, the therapeutic behavior of leukemias harboring both transcriptional programs remains poorly defined. Analysis of a large AML cohort reveals a distinct patient population exhibiting concurrent HSC- and monocyte-like transcriptional signatures, which we term stem-monocytic AML. Ex vivo drug sensitivity profiling demonstrates that stem-monocytic AMLs exhibit venetoclax resistance comparable to pure monocytic disease, despite expressing HSC-like transcriptional features. Using a leukemia cell line model that recapitulates stem-monocytic AML characteristics, we show through immunophenotyping and single-cell lineage tracing that venetoclax preferentially depletes immature blasts while sparing differentiated monocytic populations. Single-cell transcriptomic and chromatin accessibility analyses identify enrichment of myeloid differentiation transcription factors, particularly PU.1, in resistant populations. A targeted CRISPR knockout screen confirms that PU.1 disruption induces differentiation arrest and enhances venetoclax sensitivity primarily in the immature immunophenotypic compartments. Pharmacologic PU.1 inhibition with the small molecule DB2313 synergizes with venetoclax in both cell line models and primary patient samples. These findings establish stem-monocytic AML as a transcriptionally and functionally distinct subtype and nominate combined PU.1 and BCL2 inhibition as a rational therapeutic strategy for improving venetoclax response in this patient population.

DOI: https://doi.org/10.64898/2026.01.20.700677
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699315. [Epub ahead of print]

Mutant ASXL1 Drives Transcriptional Activation and Repression in Human Hematopoiesis.

Madison L Hall, Aliya Quintal, Samantha Worme, Thai Nguyen, Zachary Schonrock, Mitsuhiro Tsuchiya, Sonia N Acharya, Hanqian L Carlson, Itallia V Pacentine, Shawn Shrestha, Jommel Macaraeg, Randall Armstrong, James McGann, Sara Evans-Dutson, Theresa A Lusardi, Brendan L O'Connell, Andrew C Adey, Galip Gürkan Yardimci, Julia E Maxson, Theodore P Braun.

Mutations in the epigenetic regulator ASXL1 are common in myeloid malignancies and portend a near-universally poor prognosis. While multiple mechanisms for mutant ASXL1-dependent oncogenesis have been proposed, none have been functionally validated in the context of the human hematopoietic stem cell, where these mutations almost certainly arise. Here, we extensively characterized a CRISPR-engineered human hematopoietic stem and progenitor cell model of ASXL1 mutations. In this context, mutant ASXL1 expression decreases differentiation, increases clonogenicity in serial replating experiments, and improves engraftment in immunodeficient mice. We also show that endogenous truncating mutations in ASXL1 drive protein stabilization and confirm that mutant ASXL1 is resistant to proteasomal degradation. At the transcriptional level, these phenotypes are driven by significant repression of the stress-response genes and by increased expression of bromodomain and extra-terminal family protein targets. Using protein-interaction screens, genomic and functional approaches, we link the positive transcriptional changes in ASXL1 -mutant cells to BRD4-dependent RNA polymerase II pause release and identify a mechanism for transcriptional repression via a previously uncharacterized interaction with the transcription factor MECOM. Finally, we demonstrate that ASXL1 -mutant AML exhibits increased MECOM activity consistent with our gene-editing models. Collectively, these studies highlight a highly reproducible model of mutant ASXL1 in the appropriate cell context. Further, they are the first to functionally describe the mutant ASXL1 interactome in the context of the human HSC, identifying new dependencies with therapeutic potential.

DOI: https://doi.org/10.64898/2026.01.13.699315
bioRxiv. 2026 Jan 22. pii: 2026.01.19.700325. [Epub ahead of print]

BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.

Laura López-Hernández, Stephanie J Crowley, Sara Cea-Sánchez, Ricardo de Arellano, Neetij Krishnan, Patrick Toolan-Kerr, Lynn White, Domenico Ignoti, Emily Soto-Hidalgo, Stefano Gustincich, Román González-Prieto, Luca Pandolfini, Isaia Barbieri, Patricia Altea-Manzano, Jeffrey A Magee, Jeffrey J Bednarski, Gonzalo Millán-Zambrano.

Acute myeloid leukemia (AML) is driven by a combination of genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using human AML cell lines and murine models of AML, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. We demonstrate that BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein expression. Loss of BCLAF1 reduces ATF4 protein levels, leading to downregulation of metabolic target genes and disruption of de novo amino acid biosynthesis. Furthermore, depletion of BCLAF1 sensitizes AML cells to venetoclax, a clinically relevant BCL-2 inhibitor. Together, these findings uncover a previously unrecognized role for BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, highlighting its potential as a therapeutic target.
Statement of significance: Aberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.

DOI: https://doi.org/10.64898/2026.01.19.700325
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2526334123

HSCs/MPPs as cells of origin with altered differentiation hierarchy impairing immunomicroenvironment in PML::RARA and CBFα/β fusion AML.

Niu Qiao, Zi-Xuan Wang, Yu-Liang Zhang, Liu-Qing-Qing Zhang, Hong-Ming Zhu, Xiang-Qin Weng, Yong-Mei Zhu, Wen-Yan Cheng, Jian-Feng Li, Lu Jiang, Xiao-Yu Yan, Guang Yang, Yang Shen, Sheng-Yue Wang, Zhu Chen, Xiao-Jian Sun, Feng Liu, Sai-Juan Chen.

  The theoretical possibility for leukemia stem cells (LSCs) to produce both leukemia blasts and dysfunctional immune cells remains underexplored. Here, we investigate three major fusion transcription factor (fTF)-driven acute myeloid leukemia (AML) subtypes [RUNX1(CBFα)::RUNX1T1, PML::RARA, and CBFB::MYH11] using two optimized single-cell RNA-sequencing technologies to trace fTF expression in 24 de novo AML patients. We demonstrate that the fTFs are widely expressed not only in leukemia blasts but also in differentiated myeloid and lymphoid cells, indicating hematopoietic stem cells or multipotent progenitors (HSCs/MPPs) as LSCs that propagate altered cellular differentiation hierarchies, including immune cells. DNA-FISH confirms the presence of fTFs in T lymphoid and erythroid cells, and targeted sequencing of secondary mutations in sublineages of cells corroborates hierarchical and stepwise leukemogenesis. By tracking RUNX1::RUNX1T1-expressing cells in patients with or without relapse post-frontline chemotherapy, we highlight the necessity of eradicating LSCs to achieve sustained long-term complete remission and restore a functional immune system capable of suppressing residual disease over time. Comparative single-cell transcriptome analyses further reveal that fTFs are associated with AML subtype-specific differentiation defects in both innate and adaptive immune compartments, suggesting an altered landscape of immune cell-cell communication networks that may facilitate the survival and proliferation of leukemic blasts. Through the examination of intercellular communications among various putative fTF+ and normal cell populations, we developed a ligand-receptor (L-R)-based risk-scoring model with independent prognostic value. Collectively, these findings provide insights into the cells of origin of LSCs and the implications of fTF expression for the immune landscape of AML.

Keywords:  acute myeloid leukemia; fusion transcription factor; leukemia stem cell; single-cell RNA sequencing; subtype-specific characteristics

DOI:  https://doi.org/10.1073/pnas.2526334123
Transplant Cell Ther. 2026 Feb 02. pii: S2666-6367(26)00065-5. [Epub ahead of print]

Simultaneous NOD1 and NOD2 Deletion in Hematopoietic Stem and Progenitor cells Promotes Long-Term Donor Chimerism.

A A Hawkes, S G Kasimsetty, H Li, G P Morris, S M Kurian, S Almeida, S E DeWolf, D B McKay.

   BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains limited by inefficient donor cell engraftment, which is influenced by inflammatory stress responses triggered during conditioning and immune reconstitution. While immune-mediated barriers have been extensively studied, the molecular regulators within donor hematopoietic stem and progenitor cells (HSPCs) that influence engraftment efficiency remain less defined. NOD1 and NOD2 are cytosolic pattern recognition receptors (PRRs) traditionally known for sensing bacterial peptidoglycans and initiating innate immune signaling. However, emerging data suggest that NOD1/2 signaling may be directly activated by cellular stressors that intersect with cellular stress pathways critical to HSPC function. Our previous work has demonstrated that NOD1 and NOD2 play a critical role in modulating sterile inflammation, a key component of the transplant environment. This positions these PRRs as potential regulators of HSPC stress responses and survival during transplantation. Despite this, the cell-intrinsic role of NOD1 and NOD2 in donor HSPC engraftment has not been fully explored. Understanding how these innate immune sensors influence HSPC function in the absence of infection could reveal novel strategies to improve engraftment and long-term chimerism following HSCT.
OBJECTIVE: This study aims to determine whether the cytosolic pattern recognition receptors NOD1 and NOD2 intrinsically regulate hematopoietic stem cell reconstitution and to define the underlying mechanisms by which their deletion may enhance donor cell persistence and chimerism in transplant settings.
STUDY DESIGN: We evaluated NOD1/2 expression in murine HSPCs, tested reconstitution efficiency of wild-type (WT) versus NOD1/2 double knockout (NOD1×2⁻/⁻) donor cells in syngeneic and allogeneic recipients, and performed competitive transplant assays to assess cell-intrinsic effects. In addition, we tested the effect of NOD1/2 deletion in HSPCs on long-term survival, allograft rejection and tumor immunosurveillance. Transcriptomic profiling was performed to define mechanisms underlying altered reconstitution.
RESULTS: HSPCs constitutively expressed NOD1 and NOD2, and their transcription was upregulated by endotoxin and NOD ligands. Genetic deletion of NOD1/2 significantly increased donor cell reconstitution and long-term chimerism in both syngeneic and fully allogeneic recipients, with NOD1×2⁻/⁻ cells outcompeting WT cells in competitive transplantation. Enhanced chimerism was observed across bone marrow, blood, spleen, and lymph nodes, without altering immune lineage differentiation. NOD1×2⁻/⁻ chimeras showed normal survival, intact alloresponsiveness, and preserved tumor immunosurveillance. Transcriptomic profiling revealed significant reprogramming of NOD1×2⁻/⁻ donor HSPCs, with highly significant alterations in mitochondrial metabolism, inflammatory signaling, and oxidative stress responses in the NOD1×2-/- HSPCs, suggesting metabolic reprogramming as a mechanism of improved chimerism.
CONCLUSIONS: NOD1 and NOD2 act as innate immune checkpoints that restrict donor HSPC reconstitution. Their simultaneous absence enhances chimerism without compromising immune defense or tolerance and reprograms stem cell metabolism to favor survival. Targeting NOD1/2 signaling may represent a novel strategy to improve hematopoietic stem cell transplantation outcomes.

Keywords:  HSPC reconstitution; NOD1; NOD2; long-term chimerism; oxidative phosphorylation/ROS; stem cell transplantation

DOI:  https://doi.org/10.1016/j.jtct.2026.01.031
bioRxiv. 2026 Jan 20. pii: 2026.01.20.700390. [Epub ahead of print]

TET2 and TP53 Mutations Cooperatively Modulate the Response to Inflammation to Promote Leukemic Transformation.

Pablo Sánchez Vela, Brianna Kelly, Claudia Brady, Jonathan Foox, Jacob Glass, Richard P Koche, Matthew Wereski, Isabelle Csete, Sebastian El Ghaity-Beckley, Bridget K Marcellino, Ross L Levine, Alan H Shih.

TET2 is a commonly mutated gene in hematologic malignancies, including as an initiating event in clonal hematopoiesis (CH). Its mutation alters hematopoietic self-renewal, differentiation, and systemic inflammation responses. TP53 mutations co-occur with TET2 mutations and are also observed in patients with high-risk clonal hematopoiesis and hematologic malignancies. Using a murine model, we found that HSPCs with both mutations initially promoted a myeloproliferative phenotype. Over time these double mutant HSPCs acquire additional genomic alternations, leading to disease progression to acute leukemias including B-ALL. We observed enhanced inflammatory signatures at transformation and identified NLRP1 as a target of TP53 activation. Decreased response to an inflammatory cell death pathway in the setting of TP53 mutation allows cells to tolerate inflammatory stress. This pathway also modifies response to chemotherapies that induce protein translational stalling. Our results identify a hematopoietic stem cell stress response pathway with implications on adaptation to inflammation and chemotherapy tolerance.
Significance: TET2 and TP53 mutations co-operate leading to advanced hematologic malignancy. TET2 mutations promote an inflammatory environment and TP53 mutation supports tolerance to this inflammatory stress.

DOI: https://doi.org/10.64898/2026.01.20.700390
Blood. 2026 Feb 03. pii: blood.2025029358. [Epub ahead of print]

Proteasome Subunit PSMD1 is a Key Therapeutic Target in Multiple Myeloma.

Ting Du, Teng Fang, Sindhu C Pillai, Arghya Ray, Minxing Wang, Xueping Wan, Kenneth Wen, Yuntong Liu, Jingyu Xu, Md Abu Musa, Xiangdong Liu, Mariateresa Fulciniti, Nikhil C Munshi, Filip Garbicz, Ruben D Carrasco, Yao Yao, Zhongkun Zhang, Yan Song, Kenneth C Anderson.

We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with siRNA, delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially impacting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies.

DOI: https://doi.org/10.1182/blood.2025029358
Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]

Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.

Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.

  Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.

Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
Mol Cell Proteomics. 2026 Jan 30. pii: S1535-9476(26)00017-4. [Epub ahead of print] 101522

High-throughput proteomic profiling to evaluate differentiation syndrome with menin inhibition.

Miriam B Garcia, Bofei Wang, Irtiza Sheikh, Georgina El Hajjar, David McCall, Cesar Nunez, Amber Gibson, Philip L Lorenzi, Ghayas C Issa, Branko Cuglievan, Hussein A Abbas.

  High-throughput proteomic profiling provides a comprehensive analysis of systemic cancer effects and tumor microenvironment interactions. Characterizing soluble proteins driving inflammation in acute myeloid leukemia (AML) offers insight into inflammatory diseases like differentiation syndrome (DS) related to AML therapies like menin inhibitors. We present our application of NUcleic acid-Linked Immuno-Sandwich Assay (NULISA), a novel technology leveraging next-generation sequencing (NGS) for high-throughput, ultra-sensitive characterization of secreted inflammatory proteins in plasma or serum. Here we report its use to identify dynamic soluble protein changes during treatment and at the time of suspected DS in pediatric AML patients treated with the menin inhibitor revumenib (NCT04065399, NCT05360160).

Keywords:  acute myeloid leukemia; differentiation syndrome; menin inhibitors; pediatric; proteomics; relapsed refractory AML

DOI:  https://doi.org/10.1016/j.mcpro.2026.101522
FEBS J. 2026 Feb 04.

Proteostasis of organelles in aging and disease.

Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.

  To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.

Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules

DOI:  https://doi.org/10.1111/febs.70439
Life Sci Alliance. 2026 Apr;pii: e202503347. [Epub ahead of print]9(4):

Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.

Lukas Lövenich, Bahareh Rahimi, Henrique Baeta, Maithreyan Kuppusamy, Moritz Walkenbach, Frederik Rastfeld, Georg Dreissen, Ronald Wein, Jörg Höhfeld, Rudolf Merkel, Pitter F Huesgen, Bernd Hoffmann.

Mammalian cells are continuously exposed to internally generated or externally applied mechanical stimuli. Mechanosensitive proteins enable cells to sense mechanical stress and induce protective mechanisms like autophagy and cytoskeletal reorientation. However, how these contribute to cellular and tissue adaptations remains largely unknown. Here, we studied the response of rat smooth muscle cells (A7r5) to uniaxial cyclic stretch. Stretching induced autophagy and adaptive actin fiber reorientation. Inhibiting autophagy using chloroquine or expressing a Bag3 (T285D-S289D) phosphosite mutant that impairs chaperone-assisted selective autophagy (CASA) delayed reorientation. Proteomic analysis revealed a depletion of cytoskeletal and focal adhesion proteins after stretching, which was attenuated by autophagy inhibition. Stretching caused a reduction in focal adhesion (FA) size, and the remodeled FAs reoriented perpendicularly to the strain direction. Concurrently, prolonged stretching activated mitochondria, and inhibiting mitochondrial ATP synthesis slowed actin reorientation, suggesting that mitochondrial activity supports the mechanoresponse. Our findings highlight the role of autophagy and mitochondria in the structural remodeling of cells upon adaptation to mechanical stress.

DOI: https://doi.org/10.26508/lsa.202503347
Nat Commun. 2026 Feb 04.

A multivalent adaptor mechanism drives the nuclear import of proteasomes.

Hanna L Brunner, Robert W Kalis, Lorenz Grundmann, Zuzana Hodáková, Zuzana Koskova, Irina Grishkovskaya, Melanie de Almeida, Matthias Hinterndorfer, Hannah Knaudt, Simon Höfflin, Florian Andersch, Harald Kotisch, Achim Dickmanns, Sara Cuylen-Haering, Johannes Zuber, David Haselbach.

Nuclear protein homeostasis, including transcription factor turnover, critically depends on the nuclear proteasomes that must be imported after cell division. This dynamic process requires AKIRIN2, a small unstructured protein whose mechanistic role has remained elusive despite its essential function. Using an integrated approach combining protein-wide saturation mutagenesis screens, cryo-EM, and biochemical reconstitution, we characterize AKIRIN2 as a scaffold protein that coordinates the assembly of an importin cluster around the proteasome. AKIRIN2 binds in multiple copies to the 20S proteasome and simultaneously interacts with importin IPO9 and the KPNA2/KPNB1 heterodimer. In the nucleus, RanGTP triggers importin dissociation, releasing the proteasome, while AKIRIN2 undergoes ubiquitin-independent degradation. Our findings reveal how AKIRIN2's multivalency facilitates the recruitment of multiple importins to the proteasome, a critical adaptation for transporting this large macromolecular complex into the nucleus and maintaining the nuclear proteome.

DOI: https://doi.org/10.1038/s41467-026-69162-0
Sci Transl Med. 2026 Feb 04. 18(835): eadu3137

Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models.

Hailin Zhang, Yueshan Li, Yin Zhao, Falu Wang, Guifeng Lin, Ting Niu, He Li, Yueyue Li, Lina Liu, Yue Liang, Yu Shen, Yuyao Yi, Hui Zhou, Shang Lou, Yishan Ye, Yanmin He, Ruicheng Yang, Rui Yao, Chenyu Tian, Pei Zhou, Mengdan Wu, Mingxin Chen, Haixing Xu, Jing You, Yi Liao, Chenlu Yang, Ailin Zhao, Chong Chen, Linli Li, Shanshan Pei, Shengyong Yang.

Dysregulation of RNA N6-methyladenosine (m6A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m6A reader. We provided a high-resolution cocrystal structure of the YTHDC1-YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m6A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m6A readers is a potential strategy in the treatment of hematologic cancers.

DOI: https://doi.org/10.1126/scitranslmed.adu3137
Genes Dev. 2026 Feb 04.

Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.

Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev.

  Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the IRX5 gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of PLAG1 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.

Keywords:  Polycomb group proteins; acute myeloid leukemia; cell growth regulation; chromatin modifications; clonal evolution; epigenetic factors; epigenome dynamics

DOI:  https://doi.org/10.1101/gad.353186.125
Cell Rep Med. 2026 Feb 03. pii: S2666-3791(26)00003-0. [Epub ahead of print] 102586

Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.

Miaomiao Liu, Tianyi Chen, Xiangjie Lin, Bowen Wu, Fujie Shi, Junya Liu, Yi Chen, Tao Zeng, Shangyu Hou, Qingfei Pan, Xuemei Wang, Yiyi Yao, Wenyu Yang, Yingchi Zhang, Jinyan Huang, Jie Jin, Yinghui Zhu, Huafeng Wang.

  Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) represents a therapeutically challenging, high-risk leukemia subtype whose comprehensive proteomic characterization remains limited. Our integrated 4D label-free proteomic analysis delineates a distinct molecular signature featuring profound oxidative phosphorylation (OxPhos) deficiency, characterized by compromised mitochondrial ATP synthesis and significant reductions in electron transport chain complexes I and IV. Single-cell RNA sequencing validation establishes that stem-like ETP-ALL populations exhibit substantially diminished ETC activity relative to T-lineage-differentiated counterparts. Pharmacological intervention using dichloroacetate to restore OxPhos functionality effectively suppresses leukemic proliferation and xenograft engraftment through ROS-mediated endoplasmic reticulum stress activation. Furthermore, we identify CD109 as an attractive immunophenotypic marker that not only distinguishes ETP-ALL from other hematologic malignancies but also defines a subset with enhanced ETC suppression and heightened metabolic vulnerability to dichloroacetate. These findings elucidate the mechanistic basis of mitochondrial dysregulation in ETP-ALL pathogenesis and nominate CD109 as a promising biomarker for targeted therapeutic strategies.

Keywords:  CD109; early T-cell precursor acute lymphoblastic leukemia; mitochondrial dysfunction; oxidative phosphorylation; proteomics

DOI:  https://doi.org/10.1016/j.xcrm.2026.102586
Exp Hematol. 2026 Jan 31. pii: S0301-472X(26)00018-4. [Epub ahead of print] 105385

Functional Equivalence of Gamma- and X-Ray Irradiation for Long-Term Peripheral Blood Chimerism and AML Transplant Outcomes in Mice.

Shawn David, Griffin J Nye, Elizabeth Eudy, Ewelina Bolcun-Filas, Jennifer J Trowbridge, Kira A Young.

  Total-body irradiation is routinely used for myeloablation prior to mouse hematopoietic cell transplant. Widespread transition from 137Cs gamma irradiators to X-ray systems has raised questions about whether these modalities yield equivalent biological outcomes. Although prior studies compared gamma and X-ray irradiation in syngeneic transplants, their performance in reciprocal congenic models and in primary acute myeloid leukemia (AML) transplant remains unclear. Here, we systematically evaluated gamma and X-ray irradiation across dose and dose-rate conditions, and tested dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. While each modality exhibited distinct early effects, both ultimately supported comparable long-term donor peripheral blood (PB) chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression. These findings indicate that, with proper dose calibration, X-ray irradiation is a functionally effective alternative to gamma irradiation for normal and malignant transplant studies. Teaser Abstract: Widespread transition from 137Cs gamma irradiators to X-ray systems for myeloablation prior to mouse hematopoietic cell transplant has raised questions about whether these modalities yield equivalent biological outcomes. Here, we systematically evaluate gamma and X-ray irradiation across dose and dose-rate conditions, and test dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. While each modality exhibited distinct early effects, both ultimately supported comparable long-term donor chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression.

Keywords:  Transplant; hematopoiesis, acute myeloid leukemia; hematopoietic stem cells; irradiation

DOI:  https://doi.org/10.1016/j.exphem.2026.105385
Eur J Haematol. 2026 Feb 06.

Targeting Ikaros and Aiolos: Next-Generation Cereblon E3 Ligase Modulators in MM.

Maria Eugenia Alvaro, Enrica Antonia Martino, Santino Caserta, Mamdouh Skafi, Antonella Bruzzese, Nicola Amodio, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Ernesto Vigna, Fortunato Morabito, Massimo Gentile.

  Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by recurrent relapses and eventual refractoriness to standard agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses. This review explores the core biological features of these agents, detailing their mechanisms of action, preclinical and clinical activity, as well as safety profile. We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell-redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.

Keywords:  Cereblon E3 ligase modulators (CELMoDs); IMiD resistance/immunomodulation; Iberdomide; Mezigdomide; multiple myeloma

DOI:  https://doi.org/10.1111/ejh.70134
Res Sq. 2026 Jan 23. pii: rs.3.rs-4669225. [Epub ahead of print]

Pediatric acute myeloid leukemia tumor composition predicts patient outcomes at diagnosis and reveals mechanisms of resistance to chemotherapy.

Pavel Sumazin, Mohammad NajafPanah, Alexandra Stevens, Michele Redell, Tsz-Kwong Man.

Although most pediatric acute myeloid leukemia (pAML) patients achieve complete remission with standard-of-care chemotherapy, overall outcomes are poor, and 40% will eventually relapse. Improved methods for risk assessment at diagnosis and alternative therapies are needed to improve outcomes for these patients. Toward these objectives, we characterized the clonal composition of pAMLs, identifying subclones that expand or transform between diagnosis and relapse. We further showed that the abundance of these expanding and transforming subclones in diagnostic samples is predictive of patient outcomes and, similarly, predicts response to chemotherapy and targeted therapies in patient samples and patient-derived xenograft models. Moreover, gene expression programs previously associated with pAML chemoresistance are recurrently elevated in these predictive subclones. Consequently, we propose a novel strategy for improving pAML risk prediction at both diagnosis and during therapy that combines the detection of outcome-predictive tumor subclones in pAML blood or bone marrow with cytogenetic biomarkers and residual disease assessment. Critically, we showed that this combination dramatically improved risk prediction, including for patients who achieve complete remission after chemotherapy. Moreover, through our analyses of outcome-predictive pAML subclones, we identified potential personalized targeted therapies for pAML patients based on the composition of their tumors.

DOI: https://doi.org/10.21203/rs.3.rs-4669225/v1
Nat Commun. 2026 Feb 04.

Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.

Victoria Stavrou, Myah Ali, Nancy Gudgeon, Emma L Bishop, Taylor Fulton-Ward, Bethany Turley, Silke Heising, Sally H Mohamed, Sofia Hain, Lorna George, Minghao Deng, Jack McCowan, Lozan Sheriff, Scott P Davies, Bryan Marzullo, Daniel A Tennant, Craig L Doig, David A Bending, Ed W Roberts, Gareth G Lavery, Rebecca A Drummond, Sarah Dimeloe.

T cell metabolism increases upon activation, underpinning immune effector functions. Nicotinamide adenine dinucleotide (NAD/H) is an essential redox cofactor for glycolysis and mitochondrial substrate oxidation. It's phosphorylation to NADP/H regulates reactive oxygen species (ROS) abundance. NAD/H levels increase upon T cell activation, but synthesis pathways and implications are not fully characterised. Here, we interrogate the role of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1), the expression of which increases upon stimulation of both human and murine CD4+ T cells. Functionally, NRK1 activity restrains activation and cytokine production of CD4+ T cells while promoting survival. These activities are linked to increased NRK1 expression in the cytoplasm, where it locally raises NAD/H levels. This supports glycolysis, but more profoundly impacts cytoplasmic NADP/H generation, thereby controlling ROS abundance and nuclear NFAT translocation. During fungal and viral infection, T-cell-intrinsic NRK1 maintains effector CD4+ T cell abundance within affected tissues and draining lymph nodes, supporting infection control. Taken together, these data confirm that subcellular regulation of immune cell metabolism determines immune responses at the level of whole organism.

DOI: https://doi.org/10.1038/s41467-026-68863-w