Experimental hematology最新文献

{"title":"A-to-I RNA editing and hematopoiesis","authors":"Zhen Liang ,&nbsp;Carl R. Walkley ,&nbsp;Jacki E. Heraud-Farlow","doi":"10.1016/j.exphem.2024.104621","DOIUrl":"10.1016/j.exphem.2024.104621","url":null,"abstract":"<div><p>Adenosine-to-inosine (A-to-I) RNA editing plays essential roles in modulating normal development and homeostasis. This process is catalyzed by adenosine deaminase acting on RNA (ADAR) family proteins. The most well-understood biological processes modulated by A-to-I editing are innate immunity and neurological development, attributed to ADAR1 and ADAR2, respectively. A-to-I editing by ADAR1 is also critical in regulating hematopoiesis. This review will focus on the role of A-to-I RNA editing and ADAR enzymes, particularly ADAR1, during normal hematopoiesis in humans and mice. Furthermore, we will discuss <em>Adar1</em> mouse models that have been developed to understand the contribution of ADAR1 to hematopoiesis and its role in innate immune pathways.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"139 ","pages":"Article 104621"},"PeriodicalIF":2.5,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004855/pdfft?md5=9862c030cef87f6a6067e3f78a40054e&pid=1-s2.0-S0301472X24004855-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SI: new culture methods in experimental hematology","authors":"Kristina Kirschner","doi":"10.1016/j.exphem.2024.104617","DOIUrl":"10.1016/j.exphem.2024.104617","url":null,"abstract":"","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"139 ","pages":"Article 104617"},"PeriodicalIF":2.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers for aging of blood – how transferable are they between mice and humans?","authors":"Vithurithra Tharmapalan ,&nbsp;Wolfgang Wagner","doi":"10.1016/j.exphem.2024.104600","DOIUrl":"10.1016/j.exphem.2024.104600","url":null,"abstract":"<div><div>Aging significantly impacts the hematopoietic system, reducing its regenerative capacity and ability to restore homeostasis after stress. Mouse models have been invaluable in studying this process due to their shorter lifespan and the ability to explore genetic, treatment, and environmental influences on aging. However, not all aspects of aging are mirrored between species. This review compares three key aging biomarkers in the hematopoietic systems of mice and humans: myeloid bias, telomere attrition, and epigenetic clocks. Myeloid bias, marked by an increased fraction of myeloid cells and decreased lymphoid cells, is a significant aging marker in mice but is scarcely observed in humans after childhood. Conversely, telomere length is a robust aging biomarker in humans, whereas mice exhibit significantly different telomere dynamics, making telomere length less reliable in the murine system. Epigenetic clocks, based on DNA methylation changes at specific genomic regions, provide precise estimates of chronologic age in both mice and humans. Notably, age-associated regions in mice and humans occur at homologous genomic locations. Epigenetic clocks, depending on the epigenetic signatures used, also capture aspects of biological aging, offering powerful tools to assess genetic and environmental impacts on aging. Taken together, not all blood aging biomarkers are transferable between mice and humans. When using murine models to extrapolate human aging, it may be advantageous to focus on aging phenomena observed in both species. In conclusion, although mouse models offer significant insights, selecting appropriate biomarkers is crucial for translating findings to human aging.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"140 ","pages":"Article 104600"},"PeriodicalIF":2.5,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of pre-enrichment strategies for mouse hematopoietic stem cell isolation and metabolomic analysis","authors":"Célina Nielsen ,&nbsp;Youzhong Liu ,&nbsp;Fleur Leguay ,&nbsp;Hernán A. Tirado ,&nbsp;Nicolas Dauguet ,&nbsp;Nick van Gastel","doi":"10.1016/j.exphem.2024.104588","DOIUrl":"10.1016/j.exphem.2024.104588","url":null,"abstract":"<div><p>Blood cell production arises from the activity of hematopoietic stem cells (HSCs), defined by their self-renewal capacity and ability to give rise to all mature blood cell types. The mouse remains one of the most studied species in hematological research, and markers to define and isolate mouse HSCs are well-established. Given the very low frequency of HSCs in the bone marrow, stem cell pre-enrichment by red blood cell lysis and magnetic cell separation is often performed as part of the isolation process to reduce sorting times. Several pre-enrichment strategies are available, differing in their speed, degree of enrichment, final cell yield, and cost. In the current study, we performed a side-by-side comparison and provide a decision tree to help researchers select a pre-enrichment strategy for mouse HSC isolation depending on their downstream application. We then compared different pre-enrichment techniques in combination with metabolomics analysis of HSCs, where speed, yield and temperature during pre-enrichment are crucial factors, and found that the choice of pre-enrichment strategy significantly impacts the number of metabolites detected and levels of individual metabolites in HSCs.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"139 ","pages":"Article 104588"},"PeriodicalIF":2.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004478/pdfft?md5=ff6edb64a7b6884a702ea1d4edb428e5&pid=1-s2.0-S0301472X24004478-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular and cellular hematopoietic stem cell specification niche","authors":"Wilson K. Clements,&nbsp;Hanane Khoury","doi":"10.1016/j.exphem.2024.104280","DOIUrl":"10.1016/j.exphem.2024.104280","url":null,"abstract":"<div><p>Hematopoietic stem cells (HSCs) are a population of tissue-specific stem cells that reside in the bone marrow of adult mammals, where they self-renew and continuously regenerate the adult hematopoietic lineages over the life of the individual. Prominence as a stem cell model and clinical usefulness have driven interest in understanding the physiologic processes that lead to the specification of HSCs during embryonic development. High-efficiency directed differentiation of HSCs by the instruction of defined progenitor cells using sequentially defined instructive molecules and conditions remains impossible, indicating that comprehensive knowledge of the complete set of precursor intermediate identities and required inductive inputs remains incompletely understood. Recently, interest in the molecular and cellular microenvironment where HSCs are specified from endothelial precursors—the “specification niche”—has increased. Here we review recent progress in understanding these niche spaces across vertebrate phyla, as well as how a better characterization of the origin and molecular phenotypes of the niche cell populations has helped inform and complicate previous understanding of signaling required for HSC emergence and maturation.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"136 ","pages":"Article 104280"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001395/pdfft?md5=ce547396dac15f71ac2de76612854c08&pid=1-s2.0-S0301472X24001395-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3001 – STRESS-SPECIFIC ERYTHROID PROGENITORS IN REGENERATIVE ERYTHROPOIESIS AND MYELOPROLIFERATIVE NEOPLASM","authors":"Lily Huang ,&nbsp;Hsi-hsien Hsieh ,&nbsp;Yue Ma ,&nbsp;Huiyu Yao ,&nbsp;Andrew DeVilbiss ,&nbsp;Stefano Comazzetto ,&nbsp;Sean Morrison","doi":"10.1016/j.exphem.2024.104289","DOIUrl":"10.1016/j.exphem.2024.104289","url":null,"abstract":"<div><p>Regenerative erythropoiesis is critical for the recovery from surgery, chemotherapy, bone marrow transplantation and infection. We identified a new erythroid progenitor with colony-forming unit-erythroid (CFU-E) activity, which we named stress CFU-E (sCFU-E). sCFU-E cells are targets of erythropoietin (Epo) and its receptor EpoR, are only expanded in erythroid stress, and are essential for the recovery of erythrocyte numbers in regenerative erythropoiesis. Interestingly, in myeloproliferative neoplasms (MPN), sCFU-E are hijacked by the oncogenic JAK2 mutant, JAK2(V617F), to drive constitutive EpoR signaling and overproduction of erythrocytes.</p><p>Mechanistically, Epo promotes sCFU-E expansion through the JAK2-STAT5 pathway by inducing the expression of IRS2, thereby engaging pro-growth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R/IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR with defective STAT5 activation. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis in mice. In samples from MPN patients, the number of sCFU-E-like cells increases, and inhibition of IGR1R/IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. Moreover, metabolomics analyses showed that sCFU-E accumulates high levels of ascorbate (vitamin C), and ascorbate accelerates sCFU-E differentiation independent of its function as an antioxidant. Epo regulates sCFU-E differentiation by inducing the expression of SLC23A2, an ascorbate transporter.</p><p>Our discovery and analysis of a novel stress-specific erythroid progenitor cell population, which connects regenerative erythropoiesis with pathogenic erythrocytosis, could offer valuable insights for developing new treatments for both anemia and MPN.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104289"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001486/pdfft?md5=237e7a8badb2733a533d65e7623dcdfd&pid=1-s2.0-S0301472X24001486-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1001 –","authors":"Emmanuelle Passegue","doi":"10.1016/j.exphem.2024.104302","DOIUrl":"10.1016/j.exphem.2024.104302","url":null,"abstract":"<div><p>No Abstract Submitted</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104302"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001619/pdfft?md5=43c66abf24f85065182b73948481ae08&pid=1-s2.0-S0301472X24001619-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2007 – INFORMING THERAPEUTIC APPROACHES FOR P53 DEFECTIVE BLOOD CANCERS","authors":"Gemma Kelly ,&nbsp;Sarah Diepstraten ,&nbsp;Yin Yuan ,&nbsp;John (Eddie) La Marca ,&nbsp;Savannah Young ,&nbsp;Catherine Chang ,&nbsp;Lauren Whelan ,&nbsp;Aisling Ross ,&nbsp;Karla Fischer ,&nbsp;Giovanna Pomilio ,&nbsp;Rhiannon Morris ,&nbsp;Angela Georgiou ,&nbsp;Veronique Litalien ,&nbsp;Fiona Brown ,&nbsp;Andrew Roberts ,&nbsp;Andreas Strasser ,&nbsp;Andrew Wei","doi":"10.1016/j.exphem.2024.104564","DOIUrl":"10.1016/j.exphem.2024.104564","url":null,"abstract":"<div><p>Mutations in the tumour suppressor TP53 are common in many cancers, including aggressive blood cancers, and confer poor responses to chemotherapy. Newer BH3-mimetic drugs, such as the BCL-2 inhibitor Venetoclax, were postulated to be effective therapy for TP53 mutant blood cancers since these drugs initiate apoptosis downstream of TP53 and therefore should function agnostic of TP53 status. However recent data from our lab and others indicate wild-type TP53 is required for maximal cancer cell killing by BH3-mimetic drugs.</p><p>Using pre-clinical models of several blood cancers and CRISPR/Cas9 approaches, we interrogated the role of TP53 in the apoptotic response to BH3-mimetic drugs. We found that TP53 is not needed for BH3-mimetics to induce apoptosis via mitochondrial outer membrane permeabilization (MOMP). However, TP53 becomes activated downstream of MOMP, leading to induction of the pro-apoptotic BH3-only proteins and a second wave of apoptosis that reinforces killing of the cancer cells. Blood cancers with mutant TP53 cannot induce this enforcing wave of apoptosis and are therefore more likely to survive and contribute to relapse.</p><p>Through these analyses we identified an alternative complementary pathway to activate apoptosis using STING agonist drugs. We found that STING agonists could induce BH3-only protein expression in a TP53-independent manner, boosting the pro-apoptotic signal. Combining STING agonists with BH3-mimetic drugs led to highly effective killing of mouse B cell lymphomas, human NK/T cell lymphomas and patient-derived Acute Myeloid Leukemia blasts, even those that were mutated for TP53. Since STING agonists are already in clinical trials to induce anti-tumour immunity, we anticipate repurposing them to boost apoptosis alongside BH3-mimetic drugs in clinical trials for blood cancer patients would be effective and relatively straight forward.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104564"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004235/pdfft?md5=b3b4f58f4ac1812f14df07970f268378&pid=1-s2.0-S0301472X24004235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2011 – SUBCLONAL MUTATIONS ALTER CORE SIGNALLING NODES AND DRUG RESPONSES IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA","authors":"Teresa Sadras ,&nbsp;Lauren Brown ,&nbsp;Paul Ekert ,&nbsp;Edwin Hawkins ,&nbsp;Rob Salomon ,&nbsp;Kaitlyn Kew","doi":"10.1016/j.exphem.2024.104568","DOIUrl":"10.1016/j.exphem.2024.104568","url":null,"abstract":"<div><p>Aberrant expression of cytokine receptor-like factor 2 (CRLF2) occurs in 5–15% of B-cell acute lymphoblastic leukaemia (B-ALL) and is associated with poor outcomes.</p><p>Approximately 50% of CRLF2+ B-ALLs also harbor activating mutations in JAK2. Coexpression of CRLF2 and mutant JAK2 results in constitutive STAT5 activation, and factor-independent transformation of B cell progenitors. The current consensus is that JAK/STAT activation is the hallmark of CRLF2 B-ALL, however JAK2 inhibitors such as Ruxolitinib have shown limited efficacy in this leukemia. We have shown that some CRLF2+ B-ALLs lacking JAK2 mutations instead harbor activating mutations in the RAS-ERK pathway (e.g. KRAS-G12D). Using single-cell sequencing of matched diagnosis and relapse patient samples, we show that in patients with both STAT and ERK activating lesions, these mutations are present in competing clones which fluctuate during disease progression. However, it remains unknown how subclonal mutations alter the signalling properties and drug responses of CRLF2+ leukemias. To investigate this, we established murine models expressing the human CRLF2 receptor complex and common JAK2 and RAS pathway mutations. Using phospho-proteomics, and high throughput drug screening we show for the first time that the combination of CRLF2 with RAS mutations activates distinct signalling networks, compared to CRLF2 combined with mutant JAK2, and that this drives unique drug dependencies that can be therapeutically leveraged. To investigate subclonal dynamics in vivo, we use advanced imaging approaches to visualise how distinct sublones engage bone marrow niche structures during development, and under pressure of chemotherapy. This work reveals novel insights into the importance of subclonal mutations on the biology of CRLF2+ B-ALL.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104568"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004272/pdfft?md5=9177018801f94e59a8cfc25151231fdd&pid=1-s2.0-S0301472X24004272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3040 – RUNX1 CIS-REGULATION AND EFFECTOR FUNCTION DURING HUMAN ENDOTHELIAL-TO-HAEMATOPOIETIC TRANSITION","authors":"Alessandro Cavallo ,&nbsp;Giorgio Anselmi ,&nbsp;Thomas A. Milne ,&nbsp;Marella F.T.R. de Bruijn","doi":"10.1016/j.exphem.2024.104362","DOIUrl":"10.1016/j.exphem.2024.104362","url":null,"abstract":"<div><p>The first haematopoietic stem and progenitor cells (HSPCs) in the embryo arise through a process known as endothelial-to-haematopoietic transition (EHT). In a subset of endothelial cells referred to as haemogenic endothelium (HE), the endothelial transcriptional programme is gradually replaced by a haematopoietic one, promoting haematopoietic commitment and ultimately EHT. This process is critically dependent on the transcription factor RUNX1. There is currently limited knowledge on the transcriptional regulation and downstream function of RUNX1 during human EHT. Here, using an in vitro human induced pluripotent stem cell (hiPSC) differentiation model, we identified five candidate EHT RUNX1 enhancers, characterised by H3K27ac and open chromatin, one of which is only accessible in HE and four are accessible in haematopoietic cells. Through gene regulatory network (GRN) analysis, performed on joint single-cell chromatin accessibility and gene expression profiling data, we identified a set of candidate upstream RUNX1 activators and repressors. These included known RUNX1 regulators (e.g. GATA2, MEIS1, EPAS1) as well as potentially novel ones. To identify the downstream target genes of RUNX1, we profiled RUNX1-binding sites genome-wide in hiPSC-derived HE, where most of these sites were not acetylated and were associated with endothelial genes, suggesting RUNX1 might directly repress the endothelial programme. Together, our data are expected to improve our understanding of the regulatory mechanisms underlying human EHT.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104362"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24002212/pdfft?md5=c05f44c38363ddf031b78f144f5ef734&pid=1-s2.0-S0301472X24002212-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}