Experimental hematology最新文献

{"title":"1028 – EXOGENOUS AND ENDOGENOUS IMMUNE TARGETING OF HEMATOLOGICAL MALIGNANCIES","authors":"Paul Thomas","doi":"10.1016/j.exphem.2024.104329","DOIUrl":"10.1016/j.exphem.2024.104329","url":null,"abstract":"<div><p>Chimeric antigen receptor-engineered T cells and bispecific antibodies have proven to be effective therapies for a range of leukemias, whereas modalities that rely on endogenous T cell responses including immune checkpoint blockade have not proven as beneficial. This has been attributed to a lack of elicited endogenous responses against relatively low mutation burden ALL and AML tumors, particularly in pediatrics. Here we will discuss the identification and characterization of endogenous fusion- and neoantigen-specific T cell responses in pediatric leukemias, as well as attempts to identify such responses arising during CAR T cell therapies via epitope spreading. Novel methods for efficiently detecting these responses will be described, along with the T cell features that characterize successful anti-tumor immunity.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104329"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001887/pdfft?md5=bbdeca7d24837bf27e43d0931868b146&pid=1-s2.0-S0301472X24001887-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087237","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":"2002 – MATRICELLULAR PROTEIN DEFICIENCY TRANSFORMS MDS TO MYELOID LEUKEMIA THROUGH INDUCTION OF TGF-Β-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION","authors":"Alvaro Cuesta-Dominguez ,&nbsp;Ioanna Mosialou ,&nbsp;Brygida Bisikirska ,&nbsp;Rossella Labella ,&nbsp;Marta Galan-Diez ,&nbsp;Abdullah Ali ,&nbsp;Diana Kotini ,&nbsp;Ziwei Chen ,&nbsp;Malgorzata Olszewska ,&nbsp;Manon Jaud ,&nbsp;Stephanie Braunstein ,&nbsp;Aaron Viny ,&nbsp;Junfei Zhao ,&nbsp;Raul Rabadan ,&nbsp;Eirini Papapetrou ,&nbsp;Azra Raza ,&nbsp;Stavroula Kousteni","doi":"10.1016/j.exphem.2024.104559","DOIUrl":"10.1016/j.exphem.2024.104559","url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) often arises from myelodysplasia (MDS), a pre-leukemic condition characterized by dysplasia and ineffective hematopoiesis. Using mouse models of MDS and AML we identified a global decrease in nucleoporin (NUP) expression that was confirmed in publicly available patient databases. shRNA-mediated downregulation of NUPs in mouse MDS HSPCs and transplantation led to fully penetrant AML with blasts in blood, bone marrow (BM) and spleen. To examine the relevance of NUPs in human disease we downregulated NUPs expression in a model of induced Pluripotent Stem Cell (iPSC)-derived HSPCs harboring the MDS-relevant SRSF2P95L and ASXL1646fs*12 mutations (SA). shNUPS-SA HSPCs overcame exhaustion and loss of CD34 expression, typical of MDS cells. Transformed cells maintained growth for as long as 10 months, acquired phenotypic characteristics of AML blasts and presented a 2.5-fold upregulation of the leukemic biomarker CD123. shNUPS-SA HSPCs engrafted in NSG mice, establishing the transformative potential of NUP downregulation in a humanized in vivo model. RNAseq analysis of HSPCs from mouse and human models of AML versus MDS and patient samples revealed upregulation of genes promoting epithelial-to-mesenchymal transition (EMT). Master regulator analysis between patient-derived MDS and AML HSPCs and their stroma identified the secreted matricellular protein Tenascin X as a candidate regulator of NUPs expression. TNXB levels decreased in BM plasma of AML as compared to MDS patients and in the BM of AML as compared to MDS mice. Mass spectrometry analysis identified the presence of a TNXB protein mainly consisting of the fibrinogen-like domain linked to active TGF-β-mediated activation of EMT. The identification of EMT as a signature of transformation in a non-solid cancer uncovers a novel pathway of AML invasiveness that could be potentially targetable.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104559"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004181/pdfft?md5=e8e9fea3bba4d8585acc501681dce505&pid=1-s2.0-S0301472X24004181-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087249","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":"2021 – TNFΑ-DRIVEN INTERPLAY BETWEEN HEMATOPOIETIC STEM CELLS AND ANTIGEN-SPECIFIC CYTOTOXIC T CELLS","authors":"Zhiqian Zheng ,&nbsp;Akiho Tsuchiya ,&nbsp;Emmanuelle Passegué ,&nbsp;Atsushi Iwama ,&nbsp;Masayuki Yamashita","doi":"10.1016/j.exphem.2024.104578","DOIUrl":"10.1016/j.exphem.2024.104578","url":null,"abstract":"<div><p>Clonal expansion of aberrant hematopoietic stem cells (HSCs) underlies many of the hematological disorders. Cells with somatic mutations can be eliminated through presentation of neoantigens on MHC class I to antigen specific CD8+ cytotoxic T lymphocytes (CTL). However, much remains to be elucidated on how HSCs and CTLs interact with each other. Here, we uncover a unique TNFα-driven interplay between HSCs and CTLs. Co-culture and adoptive transfer experiments using ovalbumin-expressing (OVA+) HSCs (Lin-/c-Kit+/Sca-1+/Flk2-/CD48-/CD150+) and OVA-specific OT-I CTLs demonstrated that OVA+ HSCs efficiently present OVA peptide on MHC class I and directly activated OT-I CTLs, making HSCs one of the most susceptible hematopoietic populations to CTL killing. Indeed, adoptive transfer of OT-I CTLs to mixed chimeric mice that harbor both WT and Jak2V617F OVA+ hematopoietic cells specifically eliminated Jak2V617F OVA+ HSC clones and cured myeloproliferative neoplasm. Intracellular FACS analyses revealed that activated OT-I CTLs produced various cytokines including IFNγ and TNFα and HSCs responded to CTL-derived cytokines to upregulate T cell-attracting chemokines such as CXCL9. Interestingly, the response of HSCs to CTL-derived TNFα was critical for CTLs to induce granzyme B, and TNFα receptor–deficient OVA+ HSCs, but not IFNγ receptor–deficient OVA+ HSCs, escaped from OT-I CTL killing. Of note, such response was unique to HSCs and not observed in granulocyte-monocyte progenitors (GMPs: Lin-/c-Kit+/Sca-1-/CD34+/FcγR+). By contrast, prior exposure to TNFα but not IL-1β or IL-6, rendered OVA+ HSCs, but not OVA+ GMPs, resistant to OT-I CTL killing largely through upregulation of PD-L1 and PD-L2. Taken together, our results reveal the robustness of HSC quality control via MHC class I-dependent interplay with CTLs and highlight TNFα as its critical but context-dependent regulator.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104578"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004375/pdfft?md5=46da7ce098574941d68d504e08f9b957&pid=1-s2.0-S0301472X24004375-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087354","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":"1017 – LIFE STAGE-DEPENDENT ALTERATION IN THE REGULATION OF HEMATOPOIETIC STEM AND PROGENITOR POPULATIONS VIA THROMBOPOIETIN SIGNALING","authors":"ayako Nakamura-Ishizu","doi":"10.1016/j.exphem.2024.104318","DOIUrl":"10.1016/j.exphem.2024.104318","url":null,"abstract":"<div><p>Hematopoietic stem cells (HSCs) are the origin of all blood cells and maintained for throughout life to ensure the homeostasis of the blood system. HSCs exhibit an innate capacity for self-renewal and differentiation, yet their cell fate differs during life-stages. HSCs are predominantly proliferative in the fetal liver yet enter cell cycle dormancy in the adult bone marrow (BM). Systemically and locally produced cytokines specify the cell fate of hematopoietic lineages within the bone marrow (BM). Deficiency in the cytokine thrombopoietin (Thpo) and its receptor Mpl results in an age-progressive decline in hematopoietic stem and progenitor cell (HSPC) and megakaryocytes (MK) number. While HSPC-driven hematopoiesis in developmental and adult-stages differ in proliferative and differentiative nature, no study has addressed whether and how hematopoietic cell sensitivity of Thpo/Mpl signaling varies during these stages. We thus generated a Mpl reporter mouse (Mpl-eGFP and MplCreERT2;CAG-LSL-EGFP) to monitor, induce and trace Mpl expression on hematopoietic cells in the fetal liver (FL)(E14.5) and adult BM. While Mpl was expressed in HSCs, multipotent progenitor (MPP) cells and lineage-specific progenitor cells in the FL, Mpl expression was restricted to HSC and early MPP populations upon short-term (7days after tamoxifen administration) labeling in the adult BM. Furthermore, platelet-biased HSCs but not MK erythroid progenitor (MEP) cells expressed Mpl with short term labeling. We next assessed the effect of inducing deletion of Thpo on hematopoietic cell populations in the BM using Thpofl/fl;CreERT+ (Thpo cKO) mice. Thpo cKO mice exhibited thrombocytopenia and significant decrease in plasma Thpo. BM HSCs, platelet-biased HSCs and MKP numbers sharply and significantly decreased at day7 while other progenitor cell populations retained their number until day 28 of Thpo deletion. Difference in sensitivity to Thpo may shape life-stage dependent functional variation of HSPCs and guide the transition from developmental to adult hematopoiesis.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104318"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001772/pdfft?md5=e19c24ae4dc15cdac6fa5420e5d57e52&pid=1-s2.0-S0301472X24001772-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087359","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":"2026 – A CANCER IMMUNOTHERAPY MODALITY BASED ON DENDRITIC CELL REPROGRAMMING IN VIVO","authors":"Filipe Pereira ,&nbsp;Ervin Ascic ,&nbsp;Fritiof Åkerström ,&nbsp;Malavika Sreekumar Nair ,&nbsp;André Rosa ,&nbsp;Ilia Kurochkin ,&nbsp;Olga Zimmermannova ,&nbsp;Xavier Catena ,&nbsp;Nadezhda Rotankova ,&nbsp;Charlotte Veser ,&nbsp;Michal Rudnik ,&nbsp;Tommaso Ballocci ,&nbsp;Tiffany Schärer ,&nbsp;Xiaoli Huang ,&nbsp;Emilie Renaud ,&nbsp;Marta Velasco Santiago ,&nbsp;Özcan Met ,&nbsp;David Askmyr ,&nbsp;Malin Lindstedt ,&nbsp;Lennart Greiff ,&nbsp;Fábio Rosa","doi":"10.1016/j.exphem.2024.104584","DOIUrl":"10.1016/j.exphem.2024.104584","url":null,"abstract":"<div><p>Immunotherapy leads to long-term survival of cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established long-term systemic immunity in different mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for first-in-human trials and other applications of immune cell reprogramming in vivo.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104584"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24004430/pdfft?md5=1606df2fe6cbdfc4e0de830e903f5f31&pid=1-s2.0-S0301472X24004430-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087374","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":"1013 – VARIOUS IMMUNE CELL DEVELOPMENT FROM EMBRYOS TO ADULTS","authors":"Momoko Momoko,&nbsp;Michihiro Kobayashi","doi":"10.1016/j.exphem.2024.104314","DOIUrl":"10.1016/j.exphem.2024.104314","url":null,"abstract":"<div><p>Recently, many pieces of evidence indicate that blood cell development in the embryo is more complicated than we previously thought. Old textbooks state that the first blood cells arise in the extra-embryonic yolk sac described as transient primitive hematopoiesis, followed by definitive hematopoietic stem/progenitor emergence in the aorta-gonad mesonephros (AGM) region. These HSPCs migrate to the fetal liver and maintain fetal hematopoiesis. HSCs migrate to the bone marrow before birth and establish adult-type hematopoiesis for life. However, we and others recently reported that fetal liver hematopoiesis is supported by HSC-independent hematopoietic progenitors and the fetal-derived (HSC-independent) immune cells persist into adult life much longer than we expected. Using lineage tracing mouse models, we precisely examined the percentage of HSC-derived cells in each hematopoietic lineage and found that not 100% of cells are derived from HSCs. Instead, hematopoietic cells derived from endothelial cells in the early embryo contribute to many immune cell populations. These results were also confirmed by transplantation assays. We also identified the earliest innate lymphoid progenitors in the fetal liver. These cells arise independently of HSCs and differentiate into peritoneal B-1 cells, intestinal IgA+ cells, some T cells, and mast cells. We also examined detailed BCR of fetal-derived and HSC-derived B-1 cells.</p><p>Our data display a new paradigm in which immune cells are a mixture of cells from different origins and could function differently.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104314"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001735/pdfft?md5=7253b1d29c974a3ea1250aa1568bec7a&pid=1-s2.0-S0301472X24001735-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087377","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":"1011 – UNCOVERING CONVERGENT ABERRANT SPLICING EVENTS DRIVING MYELODYSPLASTIC SYNDROME DEFECTS","authors":"Kristin Hope","doi":"10.1016/j.exphem.2024.104312","DOIUrl":"10.1016/j.exphem.2024.104312","url":null,"abstract":"<div><p>Splicing defects are a characteristic feature of myelodysplastic syndromes (MDS) and typically associate with recurrent splicing factor mutations. However, a subset of transcripts exhibit convergent abnormal splicing, occurring even in the absence of splicing-related mutations. These shared splicing events likely include common drivers of MDS hematopoietic defects, yet the functions of the resulting transcripts remain unknown. We identified a long isoform of the heterochromatin enforcer Methyl-CpG-Binding Domain 1 (MBD1), as the product of one such mutation-independent splicing event. In cord blood CD34+ cells overexpression of the MDS-associated full-length isoform (MBD1-L), containing MBD1′s 3rd CXXC domain, impaired erythroid differentiation, stalled cell cycling and promoted apoptosis while the MBD1-ΔCXXC3 isoform (MBD1-S), preferentially produced in healthy cells, did not induce these defects. Similarly, only MBD1-L impaired reconstitution capacity in vivo, particularly in the erythroid and myeloid lineages, and produced an enrichment of the MDS transcriptomic signature. We show that inclusion of the exon containing CXXC3, unique in specifically binding non-methylated CpGs, disrupts MBD1′s co-localization with heterochromatin. This triggers a striking redistribution of MBD1 from gene bodies and intergenic regions to hypomethylated promoter CpGs, resulting in widespread repression of promoter chromatin accessibility and downregulation of cell-cycle-related transcripts through its recruitment of the SETDB1:ATF7IP H3K9 methylase complex. Through knockdown or delivery of splice-switching antisense oligonucleotides targeting the CXXC3 exon into MDS cells, we confirm that targeted MBD1-L reduction inverts the quiescent, differentiation-impaired phenotype imposed by its overexpression. These findings provide evidence that mutation-independent splicing changes can drive hematopoietic dysfunction and serve as therapeutic targets in MDS.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104312"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001711/pdfft?md5=74f2656f9469499a15750d182cebafe5&pid=1-s2.0-S0301472X24001711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087379","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":"1014 – AGE-DEPENDENT STEMNESS PROGRAMS THAT DRIVE PEDIATRIC ACUTE MYELOID LEUKEMIA","authors":"Jeffrey Magee","doi":"10.1016/j.exphem.2024.104315","DOIUrl":"10.1016/j.exphem.2024.104315","url":null,"abstract":"<div><p>Pediatric acute myeloid leukemia is a genetically diverse malignancy with some mutations conveying particularly high risk for relapse and death. For example, NUP98-rearranged (NUP98r) AML occurs primarily in early to mid-childhood, and it carries an overall survival of only 10-30%. It is not clear why NUP98r AML occurs disproportionately in mid-childhood or how to more effectively treat it.</p><p>We used a combination of mouse and human models to identify self-renewal programs that sustain NUP98r AML and test whether they are engaged most efficiently during neonatal or juvenile stages of life, as might be expected based on peak age of presentation. We isolated a conserved leukemia stem cell (LSC) population. The LSC signature distinguishes NUP98r AML from other pediatric AML subtypes, and it includes new candidate targets for therapy.</p><p>Age greatly influences the capacity of pre-leukemic progenitors to self-renew, transform and give rise to LSCs. Specifically, we found that the fetal state confers an unanticipated layer of protection against NUP98r AML. NUP98::HOXA9 induction in fetal progenitors causes precocious erythroid differentiation. In contrast, NUP98::HOXA9 induction in postnatal progenitors hyperactivates self-renewal programs while preserving an otherwise normal hematopoietic differentiation trajectory. NUP98::HOXA9-expressing neonatal progenitors self-renew, form colonies and give rise to AML far more efficiently than fetal progenitors. The fetal state confers similar protection against KMT2A::MLLT1-driven AML, another high-risk subtype. Active fetal leukemia suppression may explain why fetal leukemias are exceedingly rare even when leukemogenic mutations arise before birth.</p><p>Interestingly, fetal protection does not extend to all pediatric AML oncoproteins. The infant AML driver, MNX1, causes marked expansion of fetal progenitors that dissipates almost entirely after birth. Thus, ontogeny has mutation-specific effects on self-renewal and leukemogenic potential.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104315"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001747/pdfft?md5=e69aba30d44547f90bbc4c7f50362f5d&pid=1-s2.0-S0301472X24001747-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087381","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":"3013 – LEDGF/P75 PLAYS OPPOSING ROLES IN CHEMORESISTANCE IN DIFFERENT LEUKEMIAS","authors":"Muluembet Akele ,&nbsp;Siska Van Belle ,&nbsp;Frauke Christ ,&nbsp;Zeger Debyser","doi":"10.1016/j.exphem.2024.104335","DOIUrl":"10.1016/j.exphem.2024.104335","url":null,"abstract":"<div><p>Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75) is a chromatin-associated protein involved in multiple malignancies. It tethers the MLL/KMT2A fusion protein to the chromatin and plays a critical role in the initiation and maintenance of MLL-r leukemia which mostly affects pediatric patients and is linked to a high rate of relapse and resistance to conventional chemotherapy. Moreover, LEDGF/p75 is overexpressed in AML and prostate cancer patients who are resistant to chemotherapy. We have previously shown that reduced LEDGF/p75 expression sensitizes proliferation and survival of KMT2A-r Thp1 cells to cytarabine treatment through the sphingosine-1 pathway. Here, we studied modulation of chemoresistance by LEDGF/p75 in various types of leukemia. At first, we corroborated the results in Thp1 and expanded these findings by ectopically expressing LEDGF/p75 in the KMT2A-r Molm13 cells that naturally express low levels of LEDGF/p75. Overexpression of LEDGF/p75 in those cells resulted in increased proliferation and reduced apoptosis in the presence of cytarabine. A similar result was obtained after LEDGF/p75 depletion in K562 (CML, KMT2A WT) since a 3-fold increase in sensitivity to vincristine compared to the control was found. Vincristine treated K562 LEDGF/p75 KD cells show more apoptosis and increased caspase3 expression. Interestingly, LEDGF/p75 depletion in SEM cells (ALL, KMT2A-r) resulted in 4-fold more proliferation and less apoptosis upon cytarabine treatment compared to cells expressing mock miRNA. In conclusion, LEDGF/p75 induces chemoresistance in Thp1 and K562 cells to cytarabine and vincristine respectively but sensitizes SEM cells to cytarabine. Our findings highlight the opposing role of LEDGF/p75 in modulating chemoresistance across leukemias. Targeting LEDGF/p75 may be a promising strategy to enhance chemotherapy efficacy in specific leukemic subtypes.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104335"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001942/pdfft?md5=674e3a4f84c1489bf5269314c4ad6283&pid=1-s2.0-S0301472X24001942-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087384","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":"1003 – ESTABLISHING SAMD1-DEPENDENT ACTIVITIES IN HEMATOPOIESIS AND ERYTHROPOIESIS","authors":"Kyle Hewitt","doi":"10.1016/j.exphem.2024.104304","DOIUrl":"10.1016/j.exphem.2024.104304","url":null,"abstract":"<div><p>Transitions between cell progenitors and progeny depend on precise transcriptional mechanisms to adjust gene expression programs. The sterile alpha motif-containing 1 (SAMD1) gene encodes a transcription factor which coordinates histone modifications during embryonic stem cell exit from pluripotency. SAMD1 is expressed throughout many biological systems, but its role in hematopoiesis is unknown. SAMD1 prefers to bind chromatin at unmethylated CpG islands (CGIs), where it acts primarily as a transcriptional repressor. SAMD1 interacts with and promotes the function of lysine demethylase LSD1, which blocks terminal erythropoiesis. Samd1 knockout is embryonic lethal in mice. To test Samd1 in hematopoiesis, we performed competitive transplant experiments in mice using shRNA knockdown HSCs. Samd1 knockdown versus control HSCs revealed an increase in HSC repopulation with 3.9-fold more CD45.2+ after 8 weeks. We conducted scRNA-seq and chromatin occupancy profiling in Samd1 knockdown and knockout cells, revealing that Samd1 regulated a genetic network consistent with a role in stem cell self-renewal, including the repression of erythroid-specific genes. Ongoing experiments are testing whether SAMD1 functions in partnership with the lysine demethylase LSD1 during erythropoiesis. Both SAMD1 and LSD1 are commonly upregulated in acute myeloid leukemia (AML), and high expression is correlated with poor prognosis. These mechanisms may be exploitable to improve HSC expansion ex vivo. Linking Samd1 function to signaling, transcription, or other cellular functions opens the door to translational avenues for studying the contribution of Samd1 in hematologic pathologies.</p></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"137 ","pages":"Article 104304"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301472X24001632/pdfft?md5=b6140d128a154a1392abc3ec13606e17&pid=1-s2.0-S0301472X24001632-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086823","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}