bims-mithem 2026-02-08 papers

Issue of 2026–02–08
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

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

Health Phys. 2026 Feb 02.

Evolutionary Pressures Behind the Translocation Of Hematopoiesis to the Bone Marrow Cavity in Terrestrial Vertebrates.

P Andrew Karam, Robert P Gale, James S Welsh.

Nearly 400 million years ago, vertebrate life began to transition from a purely aquatic existence to the terrestrial environment. Concurrently, exposure to ionizing radiation from cosmic and geologic sources increased substantially. Around the same time, vertebrate hematopoietic stem cells (HSCs) migrated from the liver and peri-nephric parts of the abdomen into the interior of bones. Interestingly, among today's vertebrates, only fish lack bone marrow. All other extant vertebrates maintain their HSCs in the bone marrow cavity. We propose protection from sub-lethal DNA damage to these long-lived radiation-sensitive cells because of exposure to ionizing radiation is why HSCs are sequestered with the bone marrow cavity. Our calculations support this hypothesis. Residence in the bone marrow cavity reduced exposure to penetrating background radiation and the concomitant DNA damage by at least 20%. This reduction was even more significant radio-biologically when considering the relatively hypoxic conditions within the bone marrow cavity and oxygen's role in enhancing radiogenic DNA damage. This may be particularly relevant considering the oxygen-rich atmosphere in existence at the time of transitioning to a terrestrial habitat. Given the exquisite sensitivity of HSCs and proliferating blood cells to radiation, we propose this translocation provided a selective advantage and that protection from sub-lethal radiogenic DNA damage at least partially explains translocation of hematopoietic cells to the bone marrow cavity in terrestrial vertebrates.

Keywords: bone marrow; cosmic; ionizing; radiation; shielding

DOI: https://doi.org/10.1097/HP.0000000000002086

Mol Cell Biochem. 2026 Feb 05.

Unraveling the impact of chemoradiotherapy on hematopoietic function in cancer patients: a metabolomics-driven mechanistic investigation.

Guilan Yang, Shaojun Chen, Mengzhuan Wei.

Myelosuppression, a dose-limiting toxicity affecting a substantial proportion of chemotherapy patients globally (Wilson et al in Lancet Oncol 20(6):769-780, 2019. https://doi.org/10.1016/S1470-20451930163-9) remains a major clinical barrier to curative intent therapies and long-term survival. It leads to treatment delays, dose reductions, infection-related morbidity, and mortality, thereby imposing substantial healthcare burdens and diminishing patient quality of life. Here, we integrate recent metabolomics-driven discoveries to characterize chemotherapy- and radiotherapy-induced metabolic dysregulation across glucose, amino acid, lipid, and mitochondrial pathways and delineate how these alterations impair hematopoietic stem cell (HSC) function and disrupt the bone marrow microenvironment. We further connect metabolic perturbations with functional consequences, including HSC quiescence loss, oxidative stress, stromal niche remodeling, and immune dysregulation. We highlight emerging metabolite-based biomarkers, metabolic checkpoints, and nutrient-targeted therapeutic strategies capable of preventing or mitigating myelosuppression. In addition, we discuss metabolic-pathway-specific interventions, such as amino acid deprivation therapy, ketone-mediated hematopoietic protection, and mitochondrial stress modulation, emphasizing the translational potential of precision metabolic monitoring. Our analysis underscores the central role of precision metabolomics in predicting, stratifying, and reducing treatment-related hematotoxicity, providing a mechanistic and clinically actionable framework for improving therapeutic tolerance. This metabolomics-centered perspective supports individualized intervention strategies that may ultimately enhance therapeutic index and reduce hematological complications.

Keywords: Bone marrow microenvironment; Hematopoietic stem cells; Metabolomics; Myelosuppression

DOI: https://doi.org/10.1007/s11010-026-05488-z

JCI Insight. 2026 Jan 29. pii: e195170. [Epub ahead of print]

Mitochondrial dysfunction drives natural killer cell dysfunction in systemic lupus erythematosus.

Natalia W Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol-features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.

Keywords: Autoimmune diseases; Autoimmunity; Immunology; Lupus; NK cells

DOI: https://doi.org/10.1172/jci.insight.195170

Haematologica. 2026 Feb 05.

Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies.

Scott J Beeler, Matthew J Walter, Kelly L Bolton.

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited genetic predisposition, and acquired conditions. Large-scale population and longitudinal sequencing studies have identified determinants of clonal behavior. Characterization of the natural history of CH has enabled the development of risk stratification models to identify individuals with CH at high risk for progression to MN, thereby providing a rationale for selecting patient populations best suited for therapeutic intervention trials. Emerging strategies include targeting mutation-specific vulnerabilities, modulating inflammatory pathways, reducing genotoxic therapy-induced clonal selection, and repurposing agents with efficacy in MN. In this review, we summarize current knowledge of the risk factors underlying CH development, highlight recent advances in understanding the determinants of clonal behavior including progression to MN, and discuss emerging therapeutic approaches for preventing malignant transformation and clinical trial design considerations.

DOI: https://doi.org/10.3324/haematol.2025.287488