Experimental hematology最新文献

T-cell acute lymphoblastic leukemia (T-ALL), which constitutes of 10-15% of all pediatric ALL cases, is known for its complex pathology due to pervasive genetic and chromosomal abnormalities. Although most children are successfully cured, chromosomal rearrangements involving the KMT2A gene is considered a poor prognostic factor. In a cohort of 171 pediatric T-ALL samples we have studied differences in gene and splice variant patterns in KMT2A rearranged (KMT2A-r) T-ALL compared to KMT2A negative (KMT2A-wt) T-ALL samples. Our results have identified a distinct gene expression and splice variant expression pattern in pediatric KMT2A-r patient samples including significant expression of splicing regulatory markers ESRP1 and MBNL3. Additionally, the pro-survival long transcript variant of BCL2 were upregulated in KMT2A-r compared to KMT2A-wt T-ALL samples. Lastly, increased levels of activating methylation in the promoter region of CD44 were identified followed by an upregulation of the oncogenic transcript variant CD44v3 in KMT2A-r T-ALL. Together this suggests that CD44v3 could play a potential role as gene expression-based risk stratification of KMT2A-r rearranged T-ALL and could possibly serve as a therapeutic target using splicing modulators.

Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation towards myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the update understanding of age-related changes in HSPCs and the mechanisms underlie the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.

Hematological malignancies encompass a diverse array of subtypes, contributing to substantial heterogeneity that poses challenges in predicting clinical outcomes. Leveraging the capabilities of nuclear magnetic resonance holds substantial promise in the detection of serum biomarkers and individual metabolic alterations in patients. The study involved the analysis of the sera from patients with acute myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma to investigate the impacted metabolites and their associated pathways. The quantitative 1D 1H nuclear magnetic resonance method was employed to identify alterations. Metabolite annotations were validated using 2D analyses. Discriminating chemometric models and receiver operating characteristic curves were created using the MetaboAnalyst platform. The findings revealed significant alterations in the serum levels of amino acid catabolism products, citrate cycle intermediates, and phospholipids. The acute myeloid leukemia group showed differences in glucogenic amino acids related to the glycolysis pathway, while the chronic lymphocytic leukemia and non-Hodgkin lymphoma groups displayed variances in fumarate and acetate levels linked to the citrate cycle pathway. In the leukemia groups, higher levels of products from the protein degradation pathway were observed. The biomarker panels for each malignancy group exhibited outstanding discrimination from controls. Healthy individuals differed distinctly from patients, indicating commonly observed metabolic adaptation patterns among frequent hematological malignancies. The small cohort study using nuclear magnetic resonance metabolomics in various hematological malignancy subtypes revealed significant changes in serum amino acid and protein degradation end-product levels, suggesting prolonged leukocyte lifespan and increased energy demand.

Circular RNA (circRNA) was first discovered in viruses in 1974, they are primarily formed through back-splicing, where a downstream splice donor is joined to an upstream splice acceptor, resulting in a closed circRNA transcript. Under normal conditions, most circRNAs are stably expressed, however, in pathological conditions, circRNAs can play critical roles in the disease process of multiple myeloma (MM) through mechanisms such as competing endogenous RNAs (ceRNAs), regulation of transcription and splicing, affecting protein expression and localization, and even direct encoding of peptides. In recent years, there has been increasing interest in the role of circRNAs in MM and their regulatory functions during the disease process. Numerous studies have revealed that circRNAs are involved in the pathogenesis and prognosis of MM, aiding in the identification of reliable prognostic markers and potential therapeutic targets. Therefore, this review summarizes the structural characteristics of circRNAs, and their regulatory roles in MM, and introduces the latest advancements in understanding the novel functions of circRNAs in MM.

Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (HbO₂) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased HbO₂ affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays. FT-4202, an allosteric PKR activator, stabilizes the tetrameric enzyme and increases PKR activity in human and mouse RBCs in vitro. Seven-day oral administration of FT-4202 in Berkeley SCD mice reduced 2,3-DPG, increased HbO₂ affinity, and reduced RBC sickling versus control. There were no adverse in vitro safety findings. FT-4202 offers a therapeutic opportunity to modify the course of SCD.

Diversity in the granulocyte repertoire, including neutrophils, basophils, and eosinophils, has been reported in vertebrate species. Medaka fish (Oryzias latipes) have only neutrophils; however, the storage pool of granulopoiesis tissues and the molecular mechanism of granulopoiesis in medaka fish have not been explored. Granulocyte colony-stimulating factor (G-CSF) is a cytokine responsible for neutrophil differentiation, survival, and proliferation. We performed in silico analysis to molecularly characterize the medaka G-CSF and G-CSF receptor (G-CSFR) genes. This study showed that medaka G-CSF differs considerably from human and mouse G-CSF in terms of the primary protein structure; however, the predicted tertiary structure was largely conserved. Analyses of lipopolysaccharide stimulation and G-CSF knockout and overexpression in medaka revealed that G-CSF mobilizes neutrophils into the peripheral blood. The analysis of G-CSF-deficient medaka revealed that G-CSF is involved in erythropoiesis. These findings represent an important first step toward understanding granulocyte hematopoiesis in nonmammalian species.

Our study seeks to provide a theoretical foundation for the clinical use of cold-stored platelets (CSPs) by interpreting ultrastructural images and quantitatively analyzing structural changes. CSPs, room temperature-stored platelets (RTPs), and delayed CSPs (delayed-CSPs) were continuously observed using scanning electron microscopy and transmission electron microscopy at eight time points. Super-resolution fluorescence microscopy was employed to observe changes in platelet microtubules and mitochondrial structure and function, whereas platelet counts, metabolism, and relevant functional indicators were measured concurrently. Quantitative statistical analysis of platelet size, morphology, canalicular systems, and five organelles was performed under electron microscopy. In CSPs stored for 1 day, the platelet shape changed from circular or elliptical to spherical, with size decreasing from 2.8 × 2.2 µm to 2.0 × 2.0 µm. CSPs exhibited wrinkling and reorganization of platelet microtubule proteins, with organelles aggregating toward the central region. CSPs stored for 14 days and delayed-CSPs for stored for 10 days exhibited numerous structurally intact and active cells. The percentage of structure-intact active cells was 92% in both groups, respectively. RTPs stored for 5 and 7 days showed minimal changes in size, a normal microtubule skeleton, and were primarily in a resting state. However, RTPs stored for 10 and 14 days displayed swelling, irregular disintegration of the microtubule skeleton, and the presence of membranous structures and vacuolated cells. The percentage of structure-intact active cells was only 45% and 7%, respectively. Our findings confirmed that the maximum storage time of platelets was 5-7 days for RTPs, within 10 days for delayed-CSPs, and 14 days for CSPs.

The microbiome is a highly complex and diverse symbiotic component that undergoes dynamic changes with the organismal aging. Microbial perturbations, termed dysbiosis, exert strong influence on dysregulating the bone marrow niche and subsequently promoting the aging of hematopoietic and immune system. Accumulating studies have revealed the substantial impact of intestinal microbiome on the initiation and progression of age-related hematologic alteration and diseases, such as clonal hematopoiesis and blood cancers. Current therapeutic approaches to restore the altered microbiome diversity target specific pathobionts and are demonstrated to improve clinical outcomes of antihematologic malignancy treatments. In this review, we discuss the interplay between the microbiome and the hemato-immune system during aging process. We also shed light on the emerging therapeutic strategies to tackle the dysbiosis for amelioration of aging and disease progression.

Aging exerts a profound impact on the hematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, thrombotic events, and hematologic malignancies. Within the field of experimental hematology, the functional decline of hematopoietic stem cells (HSCs) is often regarded as a primary driver of age-related hematologic conditions. However, aging is clearly a complex multifaceted process involving not only HSCs but also mature blood cells and their interactions with other tissues. This review reappraises an HSC-centric view of hematopoietic aging by exploring how the entire hematopoietic hierarchy, from stem cells to mature cells, contributes to age-related disorders. It highlights the decline of both innate and adaptive immunity, leading to increased susceptibility to infections and cancer, and the rise of autoimmunity as peripheral immune cells undergo aging-induced changes. It explores the concept of "inflammaging," where persistent, low-grade inflammation driven by old immune cells creates a cycle of tissue damage and disease. Additionally, this review delves into the roles of inflammation and homeostatic regulation in age-related conditions such as thrombotic events and anemia, arguing that these issues arise from broader dysfunctions rather than stemming from HSC functional attrition alone. In summary, this review highlights the importance of taking a holistic approach to studying hematopoietic aging and its related pathologies. By looking beyond just stem cells and considering the full spectrum of age-associated changes, one can better capture the complexity of aging and attempt to develop preventative or rejuvenation strategies that target multiple facets of this process.