Experimental hematology最新文献

{"title":"1005 – SWITCHING GENES ON AND OFF DURING HAEMATOPOIESIS","authors":"Douglas Higgs ,&nbsp;Felice Tsang ,&nbsp;Lucy Cornell ,&nbsp;Ed Tunnacliffe ,&nbsp;Mira Kassouf","doi":"10.1016/j.exphem.2024.104306","DOIUrl":"10.1016/j.exphem.2024.104306","url":null,"abstract":"<div><p>We study how transcriptional and epigenetic programmes are played out on chromatin spanning the alpha globin cluster as hematopoietic cells undergo lineage fate decisions and differentiation to form erythroid cells. The alpha globin cluster and its regulatory elements are silenced in early progenitors, poised for expression in later progenitors and fully expressed during terminal erythroid differentiation. Using a variety of approaches we have established the order in which silencing factors are removed, activating transcription factors bind and epigenetic modifications occur. In addition, we have shown how chromosomal conformation and nuclear sub-localisation change during hematopoiesis. Detailed experimental analysis of individual elements is providing insight into the fundamental regulatory elements of the genome. Natural cis and trans acting mutations that cause alpha thalassaemia provide additional insight into how the long-range regulatory elements may interact with the promoters of the globin genes and other flanking genes to activate their expression. Together these observations establish some of the general principles by which genes within their natural chromosomal environment are switched on and off during differentiation and development and how these processes are perturbed in human disease.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104306"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001656/pdfft?md5=864b375f5cb975b19b0110e1621b7731&pid=1-s2.0-S0301472X24001656-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086746","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":"3041 – INVESTIGATING THE ROLES OF LMO2 DURING EARLY T CELL DEVELOPMENT","authors":"Samantha Chang ,&nbsp;Boyoung Shin ,&nbsp;Ellen Rothenberg","doi":"10.1016/j.exphem.2024.104363","DOIUrl":"10.1016/j.exphem.2024.104363","url":null,"abstract":"<div><p>Lmo2 has largely been defined by its oncogenic role in T-cell acute lymphoblastic leukemia; however, Lmo2’s natural role is not fully captured by this overexpression context. We hypothesize that in normal T cell development, Lmo2 contributes to a mechanism that stalls entry into the T cell pathway by initially sequestering E proteins in a TF complex, thus preventing E protein homodimerization which would otherwise push the T cell program forward. To validate, we knocked out Lmo2 in bone marrow-derived progenitor cells and analyzed development in the OP9-Dll1 co-culture system. Previous knockout (KO) experiments were conducted at timepoints where Lmo2 is already downregulated, so we utilized input from the PVA culture system to focus on the earliest developmental stages. Lmo2-KO cells differentiated at least three days faster than controls, measured by cell surface markers, and our initial bulk RNA-seq results confirm this acceleration phenotype: CD25- Lmo2-KO cells upregulate multiple features of the T cell program, including Tcf7, Gata3, Bcl11b, Ets1, Thy1, Rag1, Rag2, Cd3 and significant transcriptional activation of the TCRg and TCRb loci. This could be explained by increased Notch1 and Notch3 expression, thus increasing sensitivity to the Notch ligand-rich environment, though the Notch-response gene Hes1 was not affected. Interestingly, certain progenitor cell program members are Lmo2-activated (Spi1, Mef2c, Bcl11a, Hhex) while other canonical members are not influenced by Lmo2 (Hoxa9, Erg, Flt3), and Lmo2 loss causes specific downregulation of the myeloid signature, including C/EBP family members, Csf3r, Csf1r, Mpo, Elane and Gzma. We explore these findings, along with E protein binding data, to reveal the many roles Lmo2 plays in controlling T cell pathway entry via E protein sequestration, altered Notch signaling and/or the persistence of competing programs.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104363"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24002224/pdfft?md5=7732a11535729215d9a9c57f4b795854&pid=1-s2.0-S0301472X24002224-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087020","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":"1020 – TRIMODAL SINGLE-CELL PROFILING REVEALS EPIGENETIC INTRATUMOR HETEROGENEITY IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL)","authors":"Marjorie Brand","doi":"10.1016/j.exphem.2024.104321","DOIUrl":"10.1016/j.exphem.2024.104321","url":null,"abstract":"<div><p>Intratumor heterogeneity (ITH) is a main cause of therapy resistance and relapse in leukemia. While genetic mutations play an important role in clonal evolution during disease development, accumulating evidence suggests that non-genetic mechanisms are also major drivers of ITH. Here we used single-cell trimodal approaches measuring simultaneously RNA, chromatin and over 150 cell surface proteins as well as gene regulatory network construction to decipher the epigenetic basis of tumor heterogeneity in T cell acute lymphoblastic leukemia (T-ALL), an aggressive cancer of thymocytes with a high relapse rate. Our results reveal an unexpected contribution of non-genetic mechanisms in the tumor-initiating process in T-ALL, and allowed us to identify patient-specific combinations of cell surface proteins with critical implications for future targeted therapies.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104321"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001802/pdfft?md5=6b22896167bf8f2fae1aae6d4fe424f7&pid=1-s2.0-S0301472X24001802-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087161","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":"2004 – A SINGLE-CELL PROTEOMICS BY MASS SPECTROMETRY BASED MAP OF THE HUMAN CD34+ HEMATOPOIETIC STEM AND PROGENITOR CELL COMPARTMENT","authors":"Bo Porse ,&nbsp;Benjamin Furtwängler ,&nbsp;Nil Uresin ,&nbsp;Sabrina Richter ,&nbsp;Mikkel Bruhn Schuster ,&nbsp;Fabian Theis ,&nbsp;Erwin Schoof","doi":"10.1016/j.exphem.2024.104561","DOIUrl":"10.1016/j.exphem.2024.104561","url":null,"abstract":"<div><p>Our ability to characterize hematopoietic differentiation has been revolutionized by novel single cell technologies of which scRNAseq is undoubtedly the most influential. While this has led to novel insights into early hematopoietic decision events, e.g. how stem cells decide on their future fates, it is important to remember that mRNA levels are only proxies for the levels of the true cellular workhorses, i.e. the proteins. Since protein levels are regulated by additional cellular events such as translational initiation, elongation and protein decay, there is not necessarily a one-to-one relationship between mRNA and protein levels. Therefore, relying only on mRNA levels for the characterization of complex biological systems comes at a risk of missing important biological information.</p><p>Here, we present the first single-cell proteomics by Mass Spectrometry (scp-MS) based map of the human CD34+ hematopoietic stem and progenitor cells (HSPCs) compartment (&gt;2,500 cells averaging approximately 1,000 proteins/cell). We used the GLUE autoencoder to integrate the scp-MS data with corresponding scRNAseq data to generate a common embedding, allowing us to compare mRNA and protein levels from similar computationally inferred cells. Trajectory analysis demonstrated high concordance between mRNA and protein levels along the granulocytic/monocytic and erythroid trajectories, whereas early HSC differentiation events were associated with significant lower concordance levels, highlighting the importance of protein-level data. We leveraged these findings to identify and validate novel regulators of early hematopoietic differentiation. This work demonstrates the feasibility and potential of scp-MS to gain novel insights into normal and, in the future, malignant hematopoiesis.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104561"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X2400420X/pdfft?md5=7b3345dc0954d7453aa177ac7013bf28&pid=1-s2.0-S0301472X2400420X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087298","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":"3004 – ACUTE MYELOID LEUKEMIA CELLS REQUIRE 18-CARBON LONG FATTY ACIDS FOR PROTEIN S-ACYLATION TO MAINTAIN MITOCHONDRIAL ACTIVITY AND METABOLIC PLASTICITY","authors":"Nick van Gastel ,&nbsp;Nithya Balasundaram ,&nbsp;Aysegül Erdem ,&nbsp;Azeem Sharda ,&nbsp;Veerle Daniels ,&nbsp;Phillip Chea ,&nbsp;Fleur Leguay ,&nbsp;Youzhong Liu ,&nbsp;Mark Keibler ,&nbsp;Charles Vidoudez ,&nbsp;Andrew Lane ,&nbsp;Sunia Trauger ,&nbsp;Gregory Stephanopoulos ,&nbsp;Anthony Letai ,&nbsp;David Scadden","doi":"10.1016/j.exphem.2024.104292","DOIUrl":"10.1016/j.exphem.2024.104292","url":null,"abstract":"<div><p>While cancer cells have been identified to have a metabolism distinct from normal cells for almost a century, the clinical success of targeting metabolic enzymes for cancer therapy remains limited. A key reason for this is the ability of cells to rewire their metabolism and adapt to the blockage of a single pathway. Here, we use acute myeloid leukemia (AML), a highly lethal blood cancer, as a model to investigate and target metabolic plasticity. We treated human AML cell lines with combinations of pharmacological compounds targeting metabolic enzymes across central carbon metabolism. An unexpected synthetic lethality was observed when AML cells were simultaneously treated with BPTES, an inhibitor of glutaminase, the rate-limiting enzyme in glutamine catabolism, and TOFA, an inhibitor of acetyl-CoA carboxylase 1, a key enzyme in de novo lipogenesis. Sensitivity to this metabolic inhibitor combination was equally seen in primary AML patient samples, but healthy hematopoietic stem and progenitor cells were not affected. Stable isotope tracing and lipidomics experiments revealed that AML cells are highly lipogenic and have a distinct lipid profile characterized by a high degree of fatty acid saturation. However, we unexpectedly found that the cytotoxic effects of TOFA are not due to its inhibition of lipogenesis, but because this compound also inhibits protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 18-carbon long fatty acids and is essential to maintain correct mitochondrial function and allow metabolic adaptation to inhibition of glutaminolysis. Extended screening further showed that not only AML, but many different cancer types are sensitive to combined inhibition of protein S-acylation and glutaminolysis, highlighting this as a promising strategy to overcome metabolic plasticity and selectively eliminate cancer cells.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104292"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001516/pdfft?md5=981f6d216a102f058a292c8861988b10&pid=1-s2.0-S0301472X24001516-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087443","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":"3009 – APELIN-MEDIATED CLONAL EXPANSION OF NICHE ENDOTHELIAL CELLS DRIVES SELECTION OF LEUKEMIC AND NORMAL HSC CLONES","authors":"Chloé Baron ,&nbsp;Serine Avagyan ,&nbsp;Olivia Mitchell ,&nbsp;Song Yang ,&nbsp;Aaron Mckenna ,&nbsp;Leonard Zon","doi":"10.1016/j.exphem.2024.104297","DOIUrl":"10.1016/j.exphem.2024.104297","url":null,"abstract":"<div><p>Hematopoietic stem and progenitor cells (HSPCs) reside in niches that provide regulatory signals for their function. HSPC clones have been examined by cellular barcoding but the clonality of niche endothelial (ECs) and stromal cells (SCs) is unknown. We hypothesized that leukemia alters niche clones to support leukemogenesis. We developed a zebrafish model of acute erythroid leukemia (AEL) by overexpression of CMYC under the blood specific promotor draculin (drl). We used the GESTALT technique to uniquely barcode single cells using CRISPR-CAS9 during embryonic development. We injected GESTALT embryos with drl:CMYC to induce AEL, barcode HSPCs and their niche. Barcode and scRNA-Seq of ECs revealed a decrease in EC clones (fc=-3.5,p&lt; 0.05) and an AEL-induced angiogenic venous EC population. AEL marrows had less SC clones (fc=-2.1,p&lt; 0.01) and scRNA-Seq of SCs revealed an increased fraction of lepr+ SCs (66 vs 24%). We hypothesized that AEL cells secrete a signal to remodel niche clones. We mined our transcriptome data for ligands upregulated in AEL cells and receptors expressed on ECs and/or SCs. We identified apelin upregulated in AEL cells (p&lt; 0.0001) and receptors aplnra/b specifically expressed on niche ECs. We tested if apelin alone could remodel the niche by overexpressing apelin in HSPCs and found fewer (p=0.004) and larger (p&lt; 0.02) EC clones. HSPC barcode analysis revealed expanded myeloid clones (p&lt; 0.0001) characterized by increased macrophage and erythroid differentiation. Immunohistochemistry on human sections revealed that acute myeloid leukemia (AML) marrows express higher levels APLN and APLNR compared to controls demonstrating the relevance of apelin signaling in human disease. Our data reveals that apelin signaling mediates AEL-induced clonal and transcriptional remodeling of niche ECs to promote disease progression.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104297"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001565/pdfft?md5=72a5230b13828fc7a893c1899a5c9e23&pid=1-s2.0-S0301472X24001565-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087445","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":"2014 – CARDIOLIPIN, MITOPHAGY AND HEMATOPOIETIC STEM CELL REGENERATION","authors":"Devyani Sharma ,&nbsp;Juying Xu ,&nbsp;Marie-Dominique Filippi","doi":"10.1016/j.exphem.2024.104571","DOIUrl":"10.1016/j.exphem.2024.104571","url":null,"abstract":"<div><p>Hematopoietic Stem Cells (HSC) are known for their regenerative potential which allowed their use in bone marrow transplantation to treat hematological disorders. However, aging results in HSC functional decline. Some consequences of HSC aging include inflammation leading to clonal hematopoiesis and myelodysplastic syndrome. The central goal of this project is to understand the mechanisms leading to HSC aging. Mitochondria are critical for HSC differentiation and homeostasis. We show that in aged HSC, mitochondria have increased sphericity, polarized network, lower mitochondrial membrane potential (MPP), but increased mass. We also show a decrease in number of lysosomes and in mitophagy events in aged HSC. A lipid trafficking assay showed an atypical pattern of lipid incorporation by mitochondria in aged HSC suggesting that mitochondrial lipids become abnormal upon aging. Cardiolipin (CL), a signature mitochondrial membrane lipid is essential to maintain mitochondrial membrane structure for optimum organelle-to-organelle interactions. We found reduced CL content in aged HSC, along with decreased protein expression of tafazzin, encoded by the gene TAZ, which is crucial for remodeling CL, compared to young. Using a doxycycline inducible, sh-RNA mediated TAZ KD mouse model, reduced Taz expression caused decreased HSC regenerative potential in competitive serial transplant assay. Furthermore, TAZ KD HSC exhibited fewer lysosomes localized near mitochondria, suggesting CL is crucial for channeling lysosomes towards mitochondria and initiating mitophagy. Incubation with a cardiolipin booster, Alcar, rescued the MPP and morphology in aged HSC. This work suggests that reduced levels of CL results in accumulation of abnormal mitochondria in aged HSC further contributing to decline in HSC functions with age.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104571"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004302/pdfft?md5=b7e79254b512c8c68a200f6994e66e37&pid=1-s2.0-S0301472X24004302-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087447","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":"Capturing embryonic hematopoiesis in temporal and spatial dimensions","authors":"","doi":"10.1016/j.exphem.2024.104257","DOIUrl":"10.1016/j.exphem.2024.104257","url":null,"abstract":"<div><p>Hematopoietic stem cells (HSCs) possess the ability to sustain the continuous production of all blood cell types throughout an organism's lifespan. Although primarily located in the bone marrow of adults, HSCs originate during embryonic development. Visualization of the birth of HSCs, their developmental trajectory, and the specific interactions with their successive niches have significantly contributed to our understanding of the biology and mechanics governing HSC formation and expansion. Intravital techniques applied to live embryos or non-fixed samples have remarkably provided invaluable insights into the cellular and anatomical origins of HSCs. These imaging technologies have also shed light on the dynamic interactions between HSCs and neighboring cell types within the surrounding microenvironment or niche, such as endothelial cells or macrophages. This review delves into the advancements made in understanding the origin, production, and cellular interactions of HSCs, particularly during the embryonic development of mice and zebrafish, focusing on studies employing (live) imaging analysis.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"136 ","pages":"Article 104257"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001164/pdfft?md5=5f607406123a0fc0b953866778b27902&pid=1-s2.0-S0301472X24001164-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426621","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":"2015 – STRUCTURAL AND FUNCTIONAL ANALYSIS OF BONE MARROW STROMAL NETWORKS DURING CHEMOTHERAPY","authors":"Ana Luísa Pereira ,&nbsp;Ute Suessbier ,&nbsp;Karolina Zielinska ,&nbsp;Anjali Vijaykumar ,&nbsp;Alvaro Gomariz ,&nbsp;Paul Büschl ,&nbsp;Patrick Helbling ,&nbsp;Stephan Isringhausen ,&nbsp;Hui Chyn Wong ,&nbsp;Takashi Nagasawa ,&nbsp;Yokomizo Tomomasa ,&nbsp;César Nombela-Arrieta","doi":"10.1016/j.exphem.2024.104572","DOIUrl":"10.1016/j.exphem.2024.104572","url":null,"abstract":"<div><p>Cytoreductive treatments, such as 5-fluorouracil (5-FU), are often used as conditioning regimens in bone marrow (BM) transplantation and cancer therapy, eliminating highly proliferative hematopoietic progenitor cells and partially damaging the BM microenvironment. While the responses of the hematopoietic compartment to irradiation and chemotherapy have been studied in detail, the impact of these treatments on specific stromal components is less understood.</p><p>Here, we employ customized 3D microscopy and image-based analytical pipelines to investigate the dynamics and kinetics of injury and repair following treatment with 5-FU on sinusoidal endothelial and arterial cells (SECs and AECs), and CXCL12-abundant reticular cells (CARc) within the regenerated BM, as well as mapping the spatial distribution of HSCs. Finally, we integrate scRNA-seq data to reveal compositional changes in stromal networks and pathways involved in tissue regeneration.</p><p>We report that i) contrary to previous reports, CARc mostly survive 5-FU treatments and their numbers remain largely unaltered as determined by 3D-QM ii) myeloablation causes severe structural damage to CARc and vascular networks and fragmentation of CARc mesh iii) despite this, SECs and CARc demonstrate significant regenerative potential, restoring structural integrity and quantitative morphometric parameters iv) the regeneration of BM stroma coincides with HSC recovery and re-entry into quiescence v) while stromal networks regain their structure, the transcriptomic landscapes of both EC and MSC subsets remain strongly perturbed even after 16 weeks post 5-FU. These findings show that stromal networks possess self-organizing capabilities for rapid structural repair, but 5-FU treatment leads to long-term molecular changes in stromal cells, potentially affecting their functional regulation of hematopoiesis and HSC maintenance.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104572"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004314/pdfft?md5=72585566b59a762552ab513086a2163e&pid=1-s2.0-S0301472X24004314-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086747","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":"3039 – SYMPATHETIC NERVES AND REACTIVE OXYGEN SPECIES REGULATE INNATE AND ADAPTIVE IMMUNE FUNCTION IN THE LEUKEMIC MICROENVIRONMENT","authors":"Randall Carpenter ,&nbsp;Farzana Begum ,&nbsp;Paul Frenette ,&nbsp;Maria Maryanovich","doi":"10.1016/j.exphem.2024.104361","DOIUrl":"10.1016/j.exphem.2024.104361","url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) is an acquired hematological malignancy resulting in the expansion of undifferentiated leukemic blasts at the expense of healthy hematopoiesis. The sympathetic nervous system (SNS) plays a key role in regulating leukemogenesis, but the precise mechanism remains unclear. We have found that in a mouse model of MLL-AF9-driven AML, ROS levels in the leukemic niche are elevated, particularly in myeloid-lineage cells. Treatment with antioxidants or genetically targeting NADPH Oxidase (NOX)-derived ROS prolonged survival and reduced leukemic burden. Inhibiting ROS in AML resulted in higher levels of CD8 cytotoxic T cell activation, suggesting that niche-derived ROS may suppress T cell activity. We hypothesize that this occurs due to a loss of sympathetic nerves. Indeed, chemical sympathectomy increased myeloid-derived ROS and reduced CD8 T cell activation in healthy and leukemic mice, and leukemic mice devoid of β2 adrenergic signaling had fewer total CD8 T cells and higher leukemic burden. The precise cell types suppressing CD8 T cells via ROS are likely to be myeloid lineage cells. Macrophages, neutrophils, and myeloid-derived suppressor cells express high levels of NOX, generate the highest levels of ROS during leukemia, and are implicated in the suppression of lymphocyte activation in other malignancies. The loss of sympathetic nerves in the bone marrow and CD8 T cell dysfunction, both which occur in patients, may be linked. Indeed, our data point to a role for the loss of SNS activity during leukemia as a driver of NOX-derived ROS production by myeloid cells and suppression of CD8 T cell responses. Promoting these beneficial neuro-immune interactions could help boost anti-AML immunity and improve survival in AML patients.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104361"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24002200/pdfft?md5=08a94150cd61ce9a0baa64f6f104a569&pid=1-s2.0-S0301472X24002200-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087016","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}