{"entity": "journal", "iuid": "d643e17dae4c4de0ac5d295d4745aa04", "timestamp": "2026-07-18T02:26:41.449Z", "links": {"self": {"href": "https://publications.scilifelab.se/journal/Blood%20Adv.json"}, "display": {"href": "https://publications.scilifelab.se/journal/Blood%20Adv"}}, "title": "Blood Adv", "issn": "2473-9537", "issn-l": "2473-9529", "publications_count": 14, "publications": [{"entity": "publication", "iuid": "c0b267b08217465e9c9d03a6ade73a43", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c0b267b08217465e9c9d03a6ade73a43.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c0b267b08217465e9c9d03a6ade73a43"}}, "title": "Dual targeting of G9a and DNMTs induces anti-tumour effects in multiple myeloma", "authors": [{"family": "Nylund", "given": "Patrick William", "initials": "PW", "orcid": "0000-0002-1274-4010", "researcher": {"href": "https://publications.scilifelab.se/researcher/683976ea3c094b198998dabb0d433f4b.json"}}, {"family": "Garrido-Zabala", "given": "Berta", "initials": "B"}, {"family": "Tziola", "given": "Stefania Iliana", "initials": "SI"}, {"family": "Mohajershojai", "given": "Tabassom", "initials": "T", "orcid": "0000-0002-7364-5470", "researcher": {"href": "https://publications.scilifelab.se/researcher/73a193b44e7c4c85997ec74c0fee29ae.json"}}, {"family": "Berglund", "given": "Hanna", "initials": "H", "orcid": "0009-0007-1754-1822", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad08d24abc17454dafb1415b1400a038.json"}}, {"family": "Muylaert", "given": "Catharina", "initials": "C"}, {"family": "Van Hemelrijck", "given": "Lien Ann", "initials": "LA"}, {"family": "Atienza P\u00e1rraga", "given": "Alba", "initials": "A"}, {"family": "Vasquez", "given": "Louella", "initials": "L", "orcid": "0000-0002-5758-6036", "researcher": {"href": "https://publications.scilifelab.se/researcher/0479eadb09d44ece8523730e1e0fd0b1.json"}}, {"family": "Jacob", "given": "Jim", "initials": "J"}, {"family": "Bergquist", "given": "Eric", "initials": "E"}, {"family": "Mart\u00edn-Subero", "given": "Jos\u00e9 Ignacio", "initials": "JI"}, {"family": "\u00d6berg", "given": "Fredrik", "initials": "F", "orcid": "0000-0003-3609-1197", "researcher": {"href": "https://publications.scilifelab.se/researcher/c68243c8cc754cdb8b380db120f3b771.json"}}, {"family": "Karlsson", "given": "Torbj\u00f6rn", "initials": "T"}, {"family": "Nestor", "given": "Marika", "initials": "M", "orcid": "0000-0003-4662-3142", "researcher": {"href": "https://publications.scilifelab.se/researcher/4e9ff7b0cad949c48c808a1dedec7fe4.json"}}, {"family": "De Bruyne", "given": "Elke", "initials": "E", "orcid": "0000-0003-4012-4617", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2715df4e920432c9723d8fdf4ff897b.json"}}, {"family": "Kalushkova", "given": "Antonia", "initials": "A"}, {"family": "Jernberg-Wiklund", "given": "Helena", "initials": "H"}], "type": "journal-article", "published": "2025-07-17", "journal": {"issn": "2473-9529", "title": "Blood Adv", "issn-l": null}, "abstract": null, "doi": "10.1182/bloodadvances.2023010571", "pmid": null, "labels": {"Bioinformatics Support, Infrastructure and Training": "Collaborative", "Bioinformatics (NBIS)": "Collaborative", "Bioinformatics Long-term Support WABI": "Collaborative"}, "xrefs": [], "notes": [], "created": "2025-08-22T08:45:25.194Z", "modified": "2025-08-22T08:45:26.051Z"}, {"entity": "publication", "iuid": "9fc684fb01ab4a8197ebfe75ca38b665", "links": {"self": {"href": "https://publications.scilifelab.se/publication/9fc684fb01ab4a8197ebfe75ca38b665.json"}, "display": {"href": "https://publications.scilifelab.se/publication/9fc684fb01ab4a8197ebfe75ca38b665"}}, "title": "Single-cell multiomics of human fetal hematopoiesis define a developmental-specific population and a fetal signature.", "authors": [{"family": "Sommarin", "given": "Mikael N E", "initials": "MNE", "orcid": "0000-0002-2581-5543", "researcher": {"href": "https://publications.scilifelab.se/researcher/bdeebff543c249689f31f956ca071905.json"}}, {"family": "Olofzon", "given": "Rasmus", "initials": "R", "orcid": "0000-0001-8079-8718", "researcher": {"href": "https://publications.scilifelab.se/researcher/1aa88864460e41a2a0fcd4f0e94b0172.json"}}, {"family": "Palo", "given": "Sara", "initials": "S"}, {"family": "Dhapola", "given": "Parashar", "initials": "P", "orcid": "0000-0002-8070-7238", "researcher": {"href": "https://publications.scilifelab.se/researcher/3b747086d7b04853bc1cca89d4a71bd2.json"}}, {"family": "Soneji", "given": "Shamit", "initials": "S", "orcid": "0000-0002-8007-2260", "researcher": {"href": "https://publications.scilifelab.se/researcher/111b2cd88bb24203968dec72996396c8.json"}}, {"family": "Karlsson", "given": "G\u00f6ran", "initials": "G"}, {"family": "B\u00f6iers", "given": "Charlotta", "initials": "C", "orcid": "0000-0002-4876-1218", "researcher": {"href": "https://publications.scilifelab.se/researcher/e33b5ec83be045c693675ab6bda2e9d0.json"}}], "type": "journal article", "published": "2023-09-26", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "7", "issue": "18", "pages": "5325-5340", "issn-l": "2473-9529"}, "abstract": "Knowledge of human fetal blood development and how it differs from adult blood is highly relevant to our understanding of congenital blood and immune disorders and childhood leukemia, of which the latter can originate in utero. Blood formation occurs in waves that overlap in time and space, adding to heterogeneity, which necessitates single-cell approaches. Here, a combined single-cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), the molecular profile of established immunophenotype-gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs), such as CD90 and CD49F, were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow data set revealed that the HSC state was less frequent in FL, whereas cells with a lymphomyeloid signature were more abundant. An erythromyeloid-primed multipotent progenitor cluster was identified, potentially representing a transient, fetal-specific population. Furthermore, differentially expressed genes between fetal and adult counterparts were specifically analyzed, and a fetal core signature was identified. The core gene set could separate subgroups of acute lymphoblastic leukemia by age, suggesting that a fetal program may be partially retained in specific subgroups of pediatric leukemia. Our detailed single-cell map presented herein emphasizes molecular and immunophenotypic differences between fetal and adult blood cells, which are of significance for future studies of pediatric leukemia and blood development in general.", "doi": "10.1182/bloodadvances.2023009808", "pmid": "37379274", "labels": {"Clinical Genomics Lund": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10506049"}, {"db": "pii", "key": "496594"}], "notes": [], "created": "2023-11-21T18:53:00.623Z", "modified": "2024-01-23T08:28:41.924Z"}, {"entity": "publication", "iuid": "cd65cb61a4fb4e6f89ead24f6c0d243c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cd65cb61a4fb4e6f89ead24f6c0d243c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cd65cb61a4fb4e6f89ead24f6c0d243c"}}, "title": "Combined GLUT1 and OXPHOS inhibition eliminates acute myeloid leukemia cells by restraining their metabolic plasticity.", "authors": [{"family": "Rodriguez-Zabala", "given": "Maria", "initials": "M"}, {"family": "Ramakrishnan", "given": "Ramprasad", "initials": "R"}, {"family": "Reinbach", "given": "Katrin", "initials": "K"}, {"family": "Ghosh", "given": "Somadri", "initials": "S"}, {"family": "Oburoglu", "given": "Leal", "initials": "L", "orcid": "0000-0003-0130-6602", "researcher": {"href": "https://publications.scilifelab.se/researcher/cac8186ea00246e6a07f421e492041e6.json"}}, {"family": "Falqu\u00e9s-Costa", "given": "Antoni", "initials": "A", "orcid": "0000-0002-5341-4472", "researcher": {"href": "https://publications.scilifelab.se/researcher/a75e19f3905e45059507c43f4722da39.json"}}, {"family": "Bellamkonda", "given": "Kishan", "initials": "K"}, {"family": "Ehinger", "given": "Mats", "initials": "M"}, {"family": "Pe\u00f1a-Mart\u00ednez", "given": "Pablo", "initials": "P", "orcid": "0000-0002-0789-6431", "researcher": {"href": "https://publications.scilifelab.se/researcher/6d675e892dfc4334bb12051e004a7711.json"}}, {"family": "Puente-Moncada", "given": "Noelia", "initials": "N", "orcid": "0000-0002-5996-2349", "researcher": {"href": "https://publications.scilifelab.se/researcher/1d4ac0bd551b4463a22e3f60470c2b6d.json"}}, {"family": "Lilljebj\u00f6rn", "given": "Henrik", "initials": "H"}, {"family": "Cammenga", "given": "J\u00f6rg", "initials": "J"}, {"family": "Pronk", "given": "Cornelis Jan", "initials": "CJ", "orcid": "0000-0002-0073-9660", "researcher": {"href": "https://publications.scilifelab.se/researcher/76e42ba48d824aa0b42e871e9f11b00a.json"}}, {"family": "Lazarevic", "given": "Vladimir", "initials": "V"}, {"family": "Fioretos", "given": "Thoas", "initials": "T"}, {"family": "Hagstr\u00f6m-Andersson", "given": "Anna K", "initials": "AK", "orcid": "0000-0002-2904-1311", "researcher": {"href": "https://publications.scilifelab.se/researcher/bc93a87c663d471ba64fc3be63212a89.json"}}, {"family": "Woods", "given": "Niels-Bjarne", "initials": "NB", "orcid": "0000-0001-6052-922X", "researcher": {"href": "https://publications.scilifelab.se/researcher/9c539424e21f41d1b006196a3b4b48bf.json"}}, {"family": "J\u00e4r\u00e5s", "given": "Marcus", "initials": "M", "orcid": "0000-0003-4080-7055", "researcher": {"href": "https://publications.scilifelab.se/researcher/65cacd8558004a8689985676a798ae90.json"}}], "type": "journal article", "published": "2023-09-26", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "7", "issue": "18", "pages": "5382-5395", "issn-l": "2473-9529"}, "abstract": "Acute myeloid leukemia (AML) is initiated and propagated by leukemia stem cells (LSCs), a self-renewing population of leukemia cells responsible for therapy resistance. Hence, there is an urgent need to identify new therapeutic opportunities targeting LSCs. Here, we performed an in vivo CRISPR knockout screen to identify potential therapeutic targets by interrogating cell surface dependencies of LSCs. The facilitated glucose transporter type 1 (GLUT1) emerged as a critical in vivo metabolic dependency for LSCs in a murine MLL::AF9-driven model of AML. GLUT1 disruption by genetic ablation or pharmacological inhibition led to suppression of leukemia progression and improved survival of mice that received transplantation with LSCs. Metabolic profiling revealed that Glut1 inhibition suppressed glycolysis, decreased levels of tricarboxylic acid cycle intermediates and increased the levels of amino acids. This metabolic reprogramming was accompanied by an increase in autophagic activity and apoptosis. Moreover, Glut1 disruption caused transcriptional, morphological, and immunophenotypic changes, consistent with differentiation of AML cells. Notably, dual inhibition of GLUT1 and oxidative phosphorylation (OXPHOS) exhibited synergistic antileukemic effects in the majority of tested primary AML patient samples through restraining of their metabolic plasticity. In particular, RUNX1-mutated primary leukemia cells displayed striking sensitivity to the combination treatment compared with normal CD34+ bone marrow and cord blood cells. Collectively, our study reveals a GLUT1 dependency of murine LSCs in the bone marrow microenvironment and demonstrates that dual inhibition of GLUT1 and OXPHOS is a promising therapeutic approach for AML.", "doi": "10.1182/bloodadvances.2023009967", "pmid": "37505194", "labels": {"Clinical Genomics Lund": "Service", "Clinical Genomics": "Service", "Swedish Metabolomics Centre": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10509671"}, {"db": "pii", "key": "497184"}], "notes": [], "created": "2023-08-30T07:04:12.928Z", "modified": "2025-10-17T13:03:13.479Z"}, {"entity": "publication", "iuid": "f610248a3f26412e8d529592c0b43cd1", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f610248a3f26412e8d529592c0b43cd1.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f610248a3f26412e8d529592c0b43cd1"}}, "title": "Ciclopirox Ethanolamine Preserves the Immature State of Human HSCs by Mediating Intracellular Iron Content.", "authors": [{"family": "Safaee Talkhoncheh", "given": "Mehrnaz", "initials": "M", "orcid": "0000-0001-8429-7566", "researcher": {"href": "https://publications.scilifelab.se/researcher/5e8e20a05c6b4af9b37e0b15ebddae0e.json"}}, {"family": "Baudet", "given": "Aur\u00e9lie", "initials": "A", "orcid": "0000-0002-3246-1819", "researcher": {"href": "https://publications.scilifelab.se/researcher/b221093f801845bf8739ae7876878643.json"}}, {"family": "Ek", "given": "Fredrik", "initials": "F"}, {"family": "Subramaniam", "given": "Agatheeswaran", "initials": "A", "orcid": "0000-0003-3966-3875", "researcher": {"href": "https://publications.scilifelab.se/researcher/5ccb1e6798b84f128c3143c8da8bd35a.json"}}, {"family": "Kao", "given": "Yun-Ruei", "initials": "YR"}, {"family": "Miharada", "given": "Natsumi", "initials": "N"}, {"family": "Karlsson", "given": "Christine", "initials": "C"}, {"family": "Oburoglu", "given": "Leal", "initials": "L", "orcid": "0000-0003-0130-6602", "researcher": {"href": "https://publications.scilifelab.se/researcher/cac8186ea00246e6a07f421e492041e6.json"}}, {"family": "Rydstr\u00f6m", "given": "Anna", "initials": "A", "orcid": "0000-0002-3404-7195", "researcher": {"href": "https://publications.scilifelab.se/researcher/1c074907dfd84c9c9d90a21fe426f1af.json"}}, {"family": "\u017demaitis", "given": "Kristijonas", "initials": "K", "orcid": "0000-0002-4098-0184", "researcher": {"href": "https://publications.scilifelab.se/researcher/d122126ea9094e1ab3c83a2265175042.json"}}, {"family": "Alattar", "given": "Abdul Ghani", "initials": "AG", "orcid": "0000-0002-0319-4416", "researcher": {"href": "https://publications.scilifelab.se/researcher/28c63e788c764cdd9c88ae3317d91ab0.json"}}, {"family": "Rak", "given": "Justyna", "initials": "J"}, {"family": "Pietras", "given": "Kristian", "initials": "K", "orcid": "0000-0001-6738-4705", "researcher": {"href": "https://publications.scilifelab.se/researcher/5be0a3ec07654822a91df964eab1d6e4.json"}}, {"family": "Olsson", "given": "Roger", "initials": "R", "orcid": "0000-0002-7107-3472", "researcher": {"href": "https://publications.scilifelab.se/researcher/f3e5a72515bf44e98f43d4690c6e577e.json"}}, {"family": "Will", "given": "Britta", "initials": "B", "orcid": "0000-0002-9534-6690", "researcher": {"href": "https://publications.scilifelab.se/researcher/dab18fe025354ada97f7f186eb48439b.json"}}, {"family": "Larsson", "given": "Jonas", "initials": "J"}], "type": "journal article", "published": "2023-07-24", "journal": {"title": "Blood Adv", "issn": "2473-9537", "issn-l": "2473-9529"}, "abstract": "Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. To elucidate regulatory mechanisms governing the maintenance and propagation of human HSCs ex vivo, we screened libraries of annotated small molecules in human cord blood (CB) cells using an optimized assay for detection of functional HSCs during culture. We found that the antifungal agent ciclopirox ethanolamine (CPX) selectively supported immature CD34+CD90+ cells during culture and enhanced their long-term in vivo repopulation capacity. Purified HSCs treated with CPX showed a reduced cell division rate and an enrichment of HSC- specific gene expression patterns. Mechanistically, we found that the HSC stimulating effect of CPX was directly mediated by chelation of the intracellular iron pool, which in turn affected iron-dependent proteins and enzymes mediating cellular metabolism and respiration. Our findings unveil a significant impact of iron homeostasis in regulation of human HSCs, with important implications for both basic HSC biology and clinical hematology.", "doi": "10.1182/bloodadvances.2023009844", "pmid": "37487020", "labels": {"Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "497023"}], "notes": [], "created": "2023-11-24T11:40:56.111Z", "modified": "2025-10-17T13:04:27.619Z"}, {"entity": "publication", "iuid": "9787b70004ea41a3aecd22371d76935d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/9787b70004ea41a3aecd22371d76935d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/9787b70004ea41a3aecd22371d76935d"}}, "title": "BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib.", "authors": [{"family": "Bonfiglio", "given": "Silvia", "initials": "S", "orcid": "0000-0002-4422-1580", "researcher": {"href": "https://publications.scilifelab.se/researcher/893715fc9cc843669563d8a9791fa6d0.json"}}, {"family": "Sutton", "given": "Lesley-Ann", "initials": "LA"}, {"family": "Ljungstr\u00f6m", "given": "Viktor", "initials": "V"}, {"family": "Capasso", "given": "Antonella", "initials": "A"}, {"family": "Pandzic", "given": "Tatjana", "initials": "T"}, {"family": "Westr\u00f6m", "given": "Simone", "initials": "S"}, {"family": "Foroughi-Asl", "given": "Hassan", "initials": "H"}, {"family": "Skaftason", "given": "Aron", "initials": "A"}, {"family": "Gellerbring", "given": "Anna", "initials": "A"}, {"family": "Lyander", "given": "Anna", "initials": "A"}, {"family": "Gandini", "given": "Francesca", "initials": "F", "orcid": "0000-0001-8930-8295", "researcher": {"href": "https://publications.scilifelab.se/researcher/41feea8a61914af89215acfc54ec1751.json"}}, {"family": "Gaidano", "given": "Gianluca", "initials": "G", "orcid": "0000-0002-4681-0151", "researcher": {"href": "https://publications.scilifelab.se/researcher/b9af4cedf69e47a5a4ecf0da0ed88c8e.json"}}, {"family": "Trentin", "given": "Livio", "initials": "L", "orcid": "0000-0003-1222-6149", "researcher": {"href": "https://publications.scilifelab.se/researcher/005d6d4e9e294ab7a1d7448c9aae45da.json"}}, {"family": "Bonello", "given": "Lisa", "initials": "L"}, {"family": "Reda", "given": "Gianluigi", "initials": "G"}, {"family": "B\u00f6d\u00f6r", "given": "Csaba", "initials": "C"}, {"family": "Stavroyianni", "given": "Niki", "initials": "N"}, {"family": "Tam", "given": "Constantine S", "initials": "CS", "orcid": "0000-0002-9759-5017", "researcher": {"href": "https://publications.scilifelab.se/researcher/2861e5af1279456c804b7da8037ebad1.json"}}, {"family": "Marasca", "given": "Roberto", "initials": "R", "orcid": "0000-0002-6431-6878", "researcher": {"href": "https://publications.scilifelab.se/researcher/a8c880bbd36f4b9bb48f13ffa060fc7e.json"}}, {"family": "Forconi", "given": "Francesco", "initials": "F", "orcid": "0000-0002-2211-1831", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad6219eb25ad4023855b634fd584f6ee.json"}}, {"family": "Panayiotidis", "given": "Panayiotis", "initials": "P", "orcid": "0000-0003-0387-3993", "researcher": {"href": "https://publications.scilifelab.se/researcher/b584b3dee8c44a6f96cb1b46a20dc416.json"}}, {"family": "Ringshausen", "given": "Ingo", "initials": "I", "orcid": "0000-0002-7247-311X", "researcher": {"href": "https://publications.scilifelab.se/researcher/e786421082ac47afbf82c976026f6ca9.json"}}, {"family": "Jaksic", "given": "Ozren", "initials": "O"}, {"family": "Frustaci", "given": "Anna Maria", "initials": "AM", "orcid": "0000-0003-2587-7901", "researcher": {"href": "https://publications.scilifelab.se/researcher/20640340bc1f449c97f6ebe8142d2540.json"}}, {"family": "Iyengar", "given": "Sunil", "initials": "S", "orcid": "0000-0003-4863-4160", "researcher": {"href": "https://publications.scilifelab.se/researcher/322cce8738a74fc586545f9d196ec38b.json"}}, {"family": "Coscia", "given": "Marta", "initials": "M", "orcid": "0000-0003-2123-7675", "researcher": {"href": "https://publications.scilifelab.se/researcher/db2cb0d5220c44a6921a263a2117a83a.json"}}, {"family": "Mulligan", "given": "Stephen P", "initials": "SP"}, {"family": "Ysebaert", "given": "Lo\u00efc", "initials": "L"}, {"family": "Strugov", "given": "Vladimir", "initials": "V"}, {"family": "Pavlovsky", "given": "Carolina", "initials": "C"}, {"family": "Walewska", "given": "Renata", "initials": "R"}, {"family": "\u00d6sterborg", "given": "Anders", "initials": "A"}, {"family": "Cortese", "given": "Diego", "initials": "D"}, {"family": "Ranghetti", "given": "Pamela", "initials": "P"}, {"family": "Baliakas", "given": "Panagiotis", "initials": "P", "orcid": "0000-0002-5634-7156", "researcher": {"href": "https://publications.scilifelab.se/researcher/17370bd509dc4b1081af5aed9e5117c7.json"}}, {"family": "Stamatopoulos", "given": "Kostas", "initials": "K", "orcid": "0000-0001-8529-640X", "researcher": {"href": "https://publications.scilifelab.se/researcher/772756566c154559b2c70c8f0f44d1ad.json"}}, {"family": "Scarf\u00f2", "given": "Lydia", "initials": "L", "orcid": "0000-0002-0844-0989", "researcher": {"href": "https://publications.scilifelab.se/researcher/47c4c336efb24d86b41c872d03836c78.json"}}, {"family": "Rosenquist", "given": "Richard", "initials": "R", "orcid": "0000-0002-9067-9058", "researcher": {"href": "https://publications.scilifelab.se/researcher/6deac213de5346c2b7cb5328bbce8568.json"}}, {"family": "Ghia", "given": "Paolo", "initials": "P", "orcid": "0000-0003-3750-7342", "researcher": {"href": "https://publications.scilifelab.se/researcher/46f24783739d44c7b73a1be28c344a35.json"}}], "type": "observational study", "published": "2023-06-27", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "7", "issue": "12", "pages": "2794-2806", "issn-l": "2473-9529"}, "abstract": "Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after \u22651 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.", "doi": "10.1182/bloodadvances.2022008821", "pmid": "36696464", "labels": {"Clinical Genomics Uppsala": "Collaborative", "Clinical Genomics": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC10279547"}, {"db": "pii", "key": "494230"}], "notes": [], "created": "2023-11-29T08:28:00.316Z", "modified": "2023-11-29T08:28:00.868Z"}, {"entity": "publication", "iuid": "c91e733931184d15a4991de3419a6d4d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c91e733931184d15a4991de3419a6d4d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c91e733931184d15a4991de3419a6d4d"}}, "title": "The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML.", "authors": [{"family": "von Palffy", "given": "Sofia", "initials": "S", "orcid": "0000-0001-5640-4037", "researcher": {"href": "https://publications.scilifelab.se/researcher/594eb39f228241efb0f055799f5eaa88.json"}}, {"family": "Thorsson", "given": "Hanna", "initials": "H"}, {"family": "Pe\u00f1a-Mart\u00ednez", "given": "Pablo", "initials": "P", "orcid": "0000-0002-0789-6431", "researcher": {"href": "https://publications.scilifelab.se/researcher/6d675e892dfc4334bb12051e004a7711.json"}}, {"family": "Puente-Moncada", "given": "Noelia", "initials": "N", "orcid": "0000-0002-5996-2349", "researcher": {"href": "https://publications.scilifelab.se/researcher/1d4ac0bd551b4463a22e3f60470c2b6d.json"}}, {"family": "Sand\u00e9n", "given": "Carl", "initials": "C", "orcid": "0000-0002-8931-9565", "researcher": {"href": "https://publications.scilifelab.se/researcher/29207805704e4660b20eebc87efe5282.json"}}, {"family": "Blom", "given": "Anna M", "initials": "AM", "orcid": "0000-0002-1348-1734", "researcher": {"href": "https://publications.scilifelab.se/researcher/c18466d1f5614ecbb63c5d4136a02466.json"}}, {"family": "Henningsson", "given": "Rasmus", "initials": "R"}, {"family": "Juliusson", "given": "Gunnar", "initials": "G"}, {"family": "King", "given": "Ben", "initials": "B", "orcid": "0000-0001-6776-8741", "researcher": {"href": "https://publications.scilifelab.se/researcher/108b9f873836471697d74d10dd9f8707.json"}}, {"family": "Landberg", "given": "Niklas", "initials": "N", "orcid": "0000-0001-6752-6507", "researcher": {"href": "https://publications.scilifelab.se/researcher/1ad422be3ea44e419662d514ca40cbbe.json"}}, {"family": "Lazarevic", "given": "Vladimir", "initials": "V", "orcid": "0000-0002-1782-4423", "researcher": {"href": "https://publications.scilifelab.se/researcher/7113f0d0569247d4ac94b73ddc6ca74e.json"}}, {"family": "Orsmark-Pietras", "given": "Christina", "initials": "C"}, {"family": "Rissler", "given": "Marianne", "initials": "M"}, {"family": "Rissler", "given": "Vendela", "initials": "V"}, {"family": "\u00c5gerstam", "given": "Helena", "initials": "H"}, {"family": "J\u00e4r\u00e5s", "given": "Marcus", "initials": "M"}, {"family": "Lilljebj\u00f6rn", "given": "Henrik", "initials": "H"}, {"family": "Fioretos", "given": "Thoas", "initials": "T"}], "type": "journal article", "published": "2023-04-11", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "7", "issue": "7", "pages": "1204-1218", "issn-l": "2473-9529"}, "abstract": "Mutated nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in \u223c30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will experience relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we report on an arrayed flow cytometry-based screen directed to 362 cell surface markers. In comparing the cell surface expression on NPM1-mutated AML cells with primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as being specifically expressed in NPM1-mutated AML. By flow cytometry and single-cell RNA sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, the stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to the activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit natural killer cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.", "doi": "10.1182/bloodadvances.2022007682", "pmid": "36383712", "labels": {"Clinical Genomics Lund": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10111354"}, {"db": "pii", "key": "493242"}], "notes": [], "created": "2023-02-20T13:51:41.288Z", "modified": "2024-01-07T18:37:55.987Z"}, {"entity": "publication", "iuid": "1d1b6e0175be40d19de12cb52e08b025", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1d1b6e0175be40d19de12cb52e08b025.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1d1b6e0175be40d19de12cb52e08b025"}}, "title": "Developmental cues license megakaryocyte priming in murine hematopoietic stem cells.", "authors": [{"family": "Kristiansen", "given": "Trine A", "initials": "TA", "orcid": "0000-0002-2703-2438", "researcher": {"href": "https://publications.scilifelab.se/researcher/d78fad8db6124ad5ad34d9e7fe7cba52.json"}}, {"family": "Zhang", "given": "Qinyu", "initials": "Q", "orcid": "0000-0001-8292-938X", "researcher": {"href": "https://publications.scilifelab.se/researcher/ce43c6262b8c48c9834051d74af92495.json"}}, {"family": "Vergani", "given": "Stefano", "initials": "S", "orcid": "0000-0003-0524-5093", "researcher": {"href": "https://publications.scilifelab.se/researcher/59d21a3e7bc4415489929d7cf067d8d4.json"}}, {"family": "Boldrin", "given": "Elena", "initials": "E", "orcid": "0000-0001-6815-3060", "researcher": {"href": "https://publications.scilifelab.se/researcher/e100e810edaf4455a4af3edb40c8fa28.json"}}, {"family": "Krausse", "given": "Niklas", "initials": "N", "orcid": "0000-0002-4954-8072", "researcher": {"href": "https://publications.scilifelab.se/researcher/86bfc6e5755045abaa7d26a5922ecdd0.json"}}, {"family": "Andr\u00e9", "given": "Oscar", "initials": "O", "orcid": "0000-0003-1732-9454", "researcher": {"href": "https://publications.scilifelab.se/researcher/8cb45098164e438f8db95715e2d46a1e.json"}}, {"family": "Nordenfelt", "given": "Pontus", "initials": "P", "orcid": "0000-0002-9481-9951", "researcher": {"href": "https://publications.scilifelab.se/researcher/7aa3418ab23a4ec48c037d6d6ddea5b5.json"}}, {"family": "Sigvardsson", "given": "Mikael", "initials": "M"}, {"family": "Bryder", "given": "David", "initials": "D", "orcid": "0000-0002-8761-4237", "researcher": {"href": "https://publications.scilifelab.se/researcher/30133810251344cb9fa3e42f0e2fd511.json"}}, {"family": "Ungerb\u00e4ck", "given": "Jonas", "initials": "J", "orcid": "0000-0002-2190-3896", "researcher": {"href": "https://publications.scilifelab.se/researcher/d8f5ebabd9b541e388d170eb9ecf10fc.json"}}, {"family": "Yuan", "given": "Joan", "initials": "J", "orcid": "0000-0001-9129-8356", "researcher": {"href": "https://publications.scilifelab.se/researcher/5fc382a53ba54d05ad5eafddd85c6b57.json"}}], "type": "journal article", "published": "2022-12-27", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "6", "issue": "24", "pages": "6228-6241", "issn-l": "2473-9529"}, "abstract": "The fetal-to-adult switch in hematopoietic stem cell (HSC) behavior is characterized by alterations in lineage output and entry into deep quiescence. Here we identify the emergence of megakaryocyte (Mk)-biased HSCs as an event coinciding with this developmental switch. Single-cell chromatin accessibility analysis reveals a ubiquitous acquisition of Mk lineage priming signatures in HSCs during the fetal-to-adult transition. These molecular changes functionally coincide with increased amplitude of early Mk differentiation events after acute inflammatory insult. Importantly, we identify LIN28B, known for its role in promoting fetal-like self-renewal, as an insulator against the establishment of an Mk-biased HSC pool. LIN28B protein is developmentally silenced in the third week of life, and its prolonged expression delays emergency platelet output in young adult mice. We propose that developmental regulation of Mk priming may represent a switch for HSCs to toggle between prioritizing self-renewal in the fetus and increased host protection in postnatal life.", "doi": "10.1182/bloodadvances.2021006861", "pmid": "35584393", "labels": {"Clinical Genomics Lund": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9792704"}, {"db": "pii", "key": "485291"}], "notes": [], "created": "2023-02-20T13:49:41.758Z", "modified": "2023-02-20T13:49:41.988Z"}, {"entity": "publication", "iuid": "8e627a82e39d4c059ca3d5e9ae6a57d8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8e627a82e39d4c059ca3d5e9ae6a57d8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8e627a82e39d4c059ca3d5e9ae6a57d8"}}, "title": "Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma.", "authors": [{"family": "Pe\u00f1a-P\u00e9rez", "given": "Luc\u00eda", "initials": "L", "orcid": "0000-0002-5044-7754", "researcher": {"href": "https://publications.scilifelab.se/researcher/111f8a8c4c6d4d2ea60e5fc76831b7fa.json"}}, {"family": "Frengen", "given": "Nicolai", "initials": "N", "orcid": "0000-0003-1834-7638", "researcher": {"href": "https://publications.scilifelab.se/researcher/0c9b75c9a3ed48dbbd4cc4fae9836623.json"}}, {"family": "Hauenstein", "given": "Julia", "initials": "J", "orcid": "0000-0001-6674-4297", "researcher": {"href": "https://publications.scilifelab.se/researcher/5bda375874844045bd86d62d3b25e071.json"}}, {"family": "Gran", "given": "Charlotte", "initials": "C"}, {"family": "Gustafsson", "given": "Charlotte", "initials": "C"}, {"family": "Eisfeldt", "given": "Jesper", "initials": "J"}, {"family": "Kierczak", "given": "Marcin", "initials": "M"}, {"family": "Taborsak-Lines", "given": "Fanny", "initials": "F", "orcid": "0000-0001-7198-5116", "researcher": {"href": "https://publications.scilifelab.se/researcher/8a3bc9c440024ec994e534c3a6627f55.json"}}, {"family": "Olsen", "given": "Remi-Andr\u00e9", "initials": "RA"}, {"family": "Wallblom", "given": "Ann", "initials": "A"}, {"family": "Krstic", "given": "Aleksandra", "initials": "A"}, {"family": "Ewels", "given": "Philip", "initials": "P"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}, {"family": "M\u00e5nsson", "given": "Robert", "initials": "R", "orcid": "0000-0003-0738-0328", "researcher": {"href": "https://publications.scilifelab.se/researcher/eafa5ad22891454298bf31a94d77175f.json"}}], "type": "journal article", "published": "2022-09-13", "journal": {"title": "Blood Adv", "issn": "2473-9537", "issn-l": "2473-9529", "volume": "6", "issue": "17", "pages": "5009-5023"}, "abstract": "Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy-number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of cells subjected to fluorescence-activated cell sorting (FACS) without DNA purification. Using this protocol, we analyzed MM cells after FACS from 37 patients with MM using lrWGS. We found high concordance between lrWGS and fluorescence in situ hybridization (FISH) for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified >150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolution of the structure of diverse SVs affecting the MYC and t(11;14) loci, causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.", "doi": "10.1182/bloodadvances.2021006720", "pmid": "35675515", "labels": {"National Genomics Infrastructure": "Service", "Bioinformatics Long-term Support WABI": "Collaborative", "Bioinformatics Support, Infrastructure and Training": "Collaborative", "NGI Stockholm (Genomics Applications)": "Collaborative", "NGI Short read": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Other": "Service", "Bioinformatics Support for Computational Resources": "Service", "Bioinformatics (NBIS)": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC9631623"}, {"db": "pii", "key": "485485"}], "notes": [], "created": "2022-08-19T08:37:59.788Z", "modified": "2024-01-16T13:48:35.011Z"}, {"entity": "publication", "iuid": "e68adec8787f41db8ded4264b7ce8368", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e68adec8787f41db8ded4264b7ce8368.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e68adec8787f41db8ded4264b7ce8368"}}, "title": "Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors.", "authors": [{"family": "Wu", "given": "Chenyan", "initials": "C", "orcid": "0000-0002-8456-3825", "researcher": {"href": "https://publications.scilifelab.se/researcher/1708f01410a54151b5a023dab8bc69b9.json"}}, {"family": "Boey", "given": "Daryl", "initials": "D", "orcid": "0000-0001-5770-3709", "researcher": {"href": "https://publications.scilifelab.se/researcher/91cccf0029194e908f7c58bae57e8c2a.json"}}, {"family": "Bril", "given": "Oscar", "initials": "O", "orcid": "0000-0002-6871-6967", "researcher": {"href": "https://publications.scilifelab.se/researcher/27c8070e026542cea4ae86ea12824482.json"}}, {"family": "Grootens", "given": "Jennine", "initials": "J"}, {"family": "Vijayabaskar", "given": "M S", "initials": "MS"}, {"family": "Sorini", "given": "Chiara", "initials": "C", "orcid": "0000-0002-6803-8377", "researcher": {"href": "https://publications.scilifelab.se/researcher/975173f37f144f06b236817e224de7f0.json"}}, {"family": "Ekoff", "given": "Maria", "initials": "M"}, {"family": "Wilson", "given": "Nicola K", "initials": "NK", "orcid": "0000-0003-0865-7333", "researcher": {"href": "https://publications.scilifelab.se/researcher/2efdaba453c24b78845cda93a7b6827e.json"}}, {"family": "Ungerstedt", "given": "Johanna S", "initials": "JS"}, {"family": "Nilsson", "given": "Gunnar", "initials": "G", "orcid": "0000-0001-6795-5512", "researcher": {"href": "https://publications.scilifelab.se/researcher/258ef97611dd4441a38e1baf2b517ecd.json"}}, {"family": "Dahlin", "given": "Joakim S", "initials": "JS", "orcid": "0000-0003-3007-9875", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d022071f86a451aba84b18fb0774461.json"}}], "type": "journal article", "published": "2022-08-09", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "6", "issue": "15", "pages": "4439-4449", "issn-l": "2473-9529"}, "abstract": "Mast cell accumulation is a hallmark of a number of diseases, including allergic asthma and systemic mastocytosis. Immunoglobulin E-mediated crosslinking of the Fc\u03b5RI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages, and controversies remain about whether Fc\u03b5RI expression appears during the mast cell progenitor stage or during terminal mast cell maturation. Here, we used single-cell transcriptomics analysis to reveal a temporal association between the appearance of Fc\u03b5RI and the mast cell gene signature in CD34+ hematopoietic progenitors in adult peripheral blood. In agreement with these data, the Fc\u03b5RI+ hematopoietic progenitors formed morphologically, phenotypically, and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating development of mast cell progenitors. Culture assays showed that interleukin-3 (IL-3) and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust Fc\u03b5RI downregulation. Taken together, we showed that Fc\u03b5RI expression appears at the progenitor stage of mast cell differentiation in peripheral blood. We also showed that external stimuli regulate Fc\u03b5RI expression of mast cell progenitors, providing a possible explanation for the variable Fc\u03b5RI expression levels during mast cell development.", "doi": "10.1182/bloodadvances.2022006969", "pmid": "35500226", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pii", "key": "485139"}, {"db": "pmc", "key": "PMC9636317"}], "notes": [], "created": "2022-11-09T15:53:59.259Z", "modified": "2024-01-16T13:48:35.428Z"}, {"entity": "publication", "iuid": "e0d583dfe4c3412cbdc9356197a1f6ac", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e0d583dfe4c3412cbdc9356197a1f6ac.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e0d583dfe4c3412cbdc9356197a1f6ac"}}, "title": "Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression.", "authors": [{"family": "Stratmann", "given": "Svea", "initials": "S", "orcid": "0000-0002-7438-9093", "researcher": {"href": "https://publications.scilifelab.se/researcher/3927efe3aaf84399b26355d92c3a15cf.json"}}, {"family": "Yones", "given": "Sara A", "initials": "SA", "orcid": "0000-0002-7201-2604", "researcher": {"href": "https://publications.scilifelab.se/researcher/17817db9549947578bbe96ba93524cf5.json"}}, {"family": "Garbulowski", "given": "Mateusz", "initials": "M", "orcid": "0000-0002-2497-194X", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad0d6d37b2a04400a8dc407fc78523ec.json"}}, {"family": "Sun", "given": "Jitong", "initials": "J"}, {"family": "Skaftason", "given": "Aron", "initials": "A"}, {"family": "Mayrhofer", "given": "Markus", "initials": "M"}, {"family": "Norgren", "given": "Nina", "initials": "N", "orcid": "0000-0002-3823-1555", "researcher": {"href": "https://publications.scilifelab.se/researcher/a14a423eff78442daffe57aff0130f33.json"}}, {"family": "Herlin", "given": "Morten Krogh", "initials": "MK", "orcid": "0000-0001-7179-4643", "researcher": {"href": "https://publications.scilifelab.se/researcher/fc2efb7b874d46879e3f34e3d7a1b8ef.json"}}, {"family": "Sundstr\u00f6m", "given": "Christer", "initials": "C", "orcid": "0000-0002-8160-5647", "researcher": {"href": "https://publications.scilifelab.se/researcher/dfac750a70664f9986b3cc06334638cc.json"}}, {"family": "Eriksson", "given": "Anna", "initials": "A"}, {"family": "H\u00f6glund", "given": "Martin", "initials": "M", "orcid": "0000-0003-2468-0226", "researcher": {"href": "https://publications.scilifelab.se/researcher/8717164448ee4e2797fefd365103ddc8.json"}}, {"family": "Palle", "given": "Josefine", "initials": "J"}, {"family": "Abrahamsson", "given": "Jonas", "initials": "J"}, {"family": "Jahnukainen", "given": "Kirsi", "initials": "K"}, {"family": "Munthe-Kaas", "given": "Monica Cheng", "initials": "MC"}, {"family": "Zeller", "given": "Bernward", "initials": "B"}, {"family": "Tamm", "given": "Katja Pokrovskaja", "initials": "KP"}, {"family": "Cavelier", "given": "Lucia", "initials": "L"}, {"family": "Komorowski", "given": "Jan", "initials": "J", "orcid": "0000-0002-0766-8789", "researcher": {"href": "https://publications.scilifelab.se/researcher/b2d1190dfa864e4089c58c864857b114.json"}}, {"family": "Holmfeldt", "given": "Linda", "initials": "L", "orcid": "0000-0003-4140-3423", "researcher": {"href": "https://publications.scilifelab.se/researcher/12b8b368e61e48d3b800516f006fbb7d.json"}}], "type": "journal article", "published": "2022-01-11", "journal": {"title": "Blood Adv", "issn": "2473-9537", "issn-l": "2473-9529", "volume": "6", "issue": "1", "pages": "152-164"}, "abstract": "Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning-based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.", "doi": "10.1182/bloodadvances.2021004962", "pmid": "34619772", "labels": {"Clinical Genomics Uppsala": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support, Infrastructure and Training": "Collaborative", "Bioinformatics Long-term Support WABI": "Collaborative", "NGI Short read": "Service", "Bioinformatics Support for Computational Resources": "Service", "Bioinformatics (NBIS)": "Collaborative", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC8753201"}, {"db": "pii", "key": "477210"}], "notes": [], "created": "2021-12-06T08:28:43.286Z", "modified": "2024-01-16T13:48:37.758Z"}, {"entity": "publication", "iuid": "179b5d4b0b2143b78005f9f39d8e5044", "links": {"self": {"href": "https://publications.scilifelab.se/publication/179b5d4b0b2143b78005f9f39d8e5044.json"}, "display": {"href": "https://publications.scilifelab.se/publication/179b5d4b0b2143b78005f9f39d8e5044"}}, "title": "Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML.", "authors": [{"family": "Mareschal", "given": "Sylvain", "initials": "S"}, {"family": "Palau", "given": "Anna", "initials": "A"}, {"family": "Lindberg", "given": "Johan", "initials": "J"}, {"family": "Ruminy", "given": "Philippe", "initials": "P"}, {"family": "Nilsson", "given": "Christer", "initials": "C"}, {"family": "Bengtz\u00e9n", "given": "Sofia", "initials": "S"}, {"family": "Engvall", "given": "Marie", "initials": "M"}, {"family": "Eriksson", "given": "Anna", "initials": "A"}, {"family": "Neddermeyer", "given": "Anne", "initials": "A"}, {"family": "Marchand", "given": "Vinciane", "initials": "V"}, {"family": "Jansson", "given": "Monika", "initials": "M"}, {"family": "Bj\u00f6rklund", "given": "My", "initials": "M"}, {"family": "Jardin", "given": "Fabrice", "initials": "F"}, {"family": "Rantalainen", "given": "Mattias", "initials": "M"}, {"family": "Lennartsson", "given": "Andreas", "initials": "A"}, {"family": "Cavelier", "given": "Lucia", "initials": "L"}, {"family": "Gr\u00f6nberg", "given": "Henrik", "initials": "H"}, {"family": "Lehmann", "given": "S\u00f6ren", "initials": "S"}], "type": "journal article", "published": "2021-02-23", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "5", "issue": "4", "pages": "1003-1016", "issn-l": "2473-9529"}, "abstract": "Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss \u2265200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.", "doi": "10.1182/bloodadvances.2020002517", "pmid": "33591326", "labels": {"Clinical Genomics Uppsala": "Collaborative", "Bioinformatics Support for Computational Resources": "Service", "Clinical Genomics": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC7903223"}, {"db": "pii", "key": "S2473-9529(21)00122-1"}], "notes": [], "created": "2021-12-06T08:29:18.429Z", "modified": "2024-01-16T13:48:40.628Z"}, {"entity": "publication", "iuid": "70655a5870824411b3765f5eee576afe", "links": {"self": {"href": "https://publications.scilifelab.se/publication/70655a5870824411b3765f5eee576afe.json"}, "display": {"href": "https://publications.scilifelab.se/publication/70655a5870824411b3765f5eee576afe"}}, "title": "Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets.", "authors": [{"family": "Stratmann", "given": "Svea", "initials": "S", "orcid": "0000-0002-7438-9093", "researcher": {"href": "https://publications.scilifelab.se/researcher/3927efe3aaf84399b26355d92c3a15cf.json"}}, {"family": "Yones", "given": "Sara A", "initials": "SA", "orcid": "0000-0002-7201-2604", "researcher": {"href": "https://publications.scilifelab.se/researcher/17817db9549947578bbe96ba93524cf5.json"}}, {"family": "Mayrhofer", "given": "Markus", "initials": "M"}, {"family": "Norgren", "given": "Nina", "initials": "N", "orcid": "0000-0002-3823-1555", "researcher": {"href": "https://publications.scilifelab.se/researcher/a14a423eff78442daffe57aff0130f33.json"}}, {"family": "Skaftason", "given": "Aron", "initials": "A"}, {"family": "Sun", "given": "Jitong", "initials": "J"}, {"family": "Smolinska", "given": "Karolina", "initials": "K", "orcid": "0000-0003-0907-5298", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f60978d8a384de0a158c0579d8b0586.json"}}, {"family": "Komorowski", "given": "Jan", "initials": "J", "orcid": "0000-0002-0766-8789", "researcher": {"href": "https://publications.scilifelab.se/researcher/b2d1190dfa864e4089c58c864857b114.json"}}, {"family": "Herlin", "given": "Morten Krogh", "initials": "MK", "orcid": "0000-0001-7179-4643", "researcher": {"href": "https://publications.scilifelab.se/researcher/fc2efb7b874d46879e3f34e3d7a1b8ef.json"}}, {"family": "Sundstr\u00f6m", "given": "Christer", "initials": "C", "orcid": "0000-0002-8160-5647", "researcher": {"href": "https://publications.scilifelab.se/researcher/dfac750a70664f9986b3cc06334638cc.json"}}, {"family": "Eriksson", "given": "Anna", "initials": "A"}, {"family": "H\u00f6glund", "given": "Martin", "initials": "M", "orcid": "0000-0003-2468-0226", "researcher": {"href": "https://publications.scilifelab.se/researcher/8717164448ee4e2797fefd365103ddc8.json"}}, {"family": "Palle", "given": "Josefine", "initials": "J"}, {"family": "Abrahamsson", "given": "Jonas", "initials": "J"}, {"family": "Jahnukainen", "given": "Kirsi", "initials": "K"}, {"family": "Munthe-Kaas", "given": "Monica Cheng", "initials": "MC"}, {"family": "Zeller", "given": "Bernward", "initials": "B"}, {"family": "Tamm", "given": "Katja Pokrovskaja", "initials": "KP"}, {"family": "Cavelier", "given": "Lucia", "initials": "L", "orcid": "0009-0003-8195-370X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f01226edb140436da0c9d166c1f5fe51.json"}}, {"family": "Holmfeldt", "given": "Linda", "initials": "L", "orcid": "0000-0003-4140-3423", "researcher": {"href": "https://publications.scilifelab.se/researcher/12b8b368e61e48d3b800516f006fbb7d.json"}}], "type": "journal article", "published": "2021-02-09", "journal": {"title": "Blood Adv", "issn": "2473-9537", "issn-l": "2473-9529", "volume": "5", "issue": "3", "pages": "900-912"}, "abstract": "Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.", "doi": "10.1182/bloodadvances.2020003709", "pmid": "33560403", "labels": {"NGI Uppsala (Uppsala Genome Center)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support, Infrastructure and Training": "Collaborative", "Bioinformatics Long-term Support WABI": "Collaborative", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "Clinical Genomics Uppsala": "Service", "Bioinformatics Support for Computational Resources": "Service", "Bioinformatics (NBIS)": "Collaborative", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "S2473-9529(21)00115-4"}, {"db": "pmc", "key": "PMC7876890"}], "notes": [], "created": "2021-02-17T19:26:48.353Z", "modified": "2024-01-16T13:48:40.749Z"}, {"entity": "publication", "iuid": "9cf391ad464e47f79d7b9e7f0c5c446b", "links": {"self": {"href": "https://publications.scilifelab.se/publication/9cf391ad464e47f79d7b9e7f0c5c446b.json"}, "display": {"href": "https://publications.scilifelab.se/publication/9cf391ad464e47f79d7b9e7f0c5c446b"}}, "title": "Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6.", "authors": [{"family": "J\u00e4rviaho", "given": "Tekla", "initials": "T"}, {"family": "Bang", "given": "Benedicte", "initials": "B"}, {"family": "Zachariadis", "given": "Vasilios", "initials": "V"}, {"family": "Taylan", "given": "Fulya", "initials": "F"}, {"family": "Moilanen", "given": "Jukka", "initials": "J"}, {"family": "M\u00f6tt\u00f6nen", "given": "Merja", "initials": "M"}, {"family": "Smith", "given": "C I Edvard", "initials": "CIE"}, {"family": "Harila-Saari", "given": "Arja", "initials": "A"}, {"family": "Niinim\u00e4ki", "given": "Riitta", "initials": "R"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}], "type": "journal article", "published": "2019-09-24", "journal": {"volume": "3", "issn": "2473-9537", "issue": "18", "pages": "2722-2731", "title": "Blood Adv", "issn-l": "2473-9529"}, "abstract": "Pathogenic germline variants in \r\n                ETV6 have been associated with familial predisposition to thrombocytopenia and hematological malignancies, predominantly childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In addition, overrepresentation of a high hyperdiploid subtype and older age at diagnosis have been reported among sporadic BCP-ALL cases with germline variants in ETV6 We studied a family with 2 second-degree relatives who developed childhood high hyperdiploid BCP-ALL at ages 8 and 12 years, respectively. A constitutional balanced reciprocal translocation t(12;14)(p13.2;q23.1) was discovered in both patients by routine karyotyping at diagnosis and, subsequently, in 7 healthy family members who had not experienced hematological malignancies. No carriers had thrombocytopenia. Whole-genome sequencing confirmed the translocation, resulting in 2 actively transcribed but nonfunctional fusion genes, causing heterozygous loss and consequently monoallelic expression of ETV6 Whole-genome sequencing analysis of the affected female subjects' leukemia excluded additional somatic aberrations in ETV6 and RTN1 as well as shared somatic variants in other genes. Expression studies, performed to confirm decreased expression of ETV6, were not conclusive. We suggest that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of ETV6 is required for developing THC5. To our knowledge, this report is the first of a constitutional translocation disrupting ETV6 causing predisposition to childhood ALL.", "doi": "10.1182/bloodadvances.2018028795", "pmid": "31519648", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pii", "key": "bloodadvances.2018028795"}], "notes": [], "created": "2019-09-16T11:35:19.734Z", "modified": "2024-01-16T13:48:43.828Z"}, {"entity": "publication", "iuid": "bafe74441a7f4f90a4fbd1cc012ed3f0", "links": {"self": {"href": "https://publications.scilifelab.se/publication/bafe74441a7f4f90a4fbd1cc012ed3f0.json"}, "display": {"href": "https://publications.scilifelab.se/publication/bafe74441a7f4f90a4fbd1cc012ed3f0"}}, "title": "Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury.", "authors": [{"family": "Kapur", "given": "Rick", "initials": "R"}, {"family": "Kim", "given": "Michael", "initials": "M"}, {"family": "Rebetz", "given": "Johan", "initials": "J"}, {"family": "Hallstr\u00f6m", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Bj\u00f6rkman", "given": "Jonas T", "initials": "JT"}, {"family": "Takabe-French", "given": "Alisa", "initials": "A"}, {"family": "Kim", "given": "Noel", "initials": "N"}, {"family": "Liu", "given": "Jonathan", "initials": "J"}, {"family": "Shanmugabhavananthan", "given": "Shanjeevan", "initials": "S"}, {"family": "Milosevic", "given": "Stefan", "initials": "S"}, {"family": "McVey", "given": "Mark J", "initials": "MJ"}, {"family": "Speck", "given": "Edwin R", "initials": "ER"}, {"family": "Semple", "given": "John W", "initials": "JW"}], "type": "journal article", "published": "2018-07-10", "journal": {"title": "Blood Adv", "issn": "2473-9537", "volume": "2", "issue": "13", "pages": "1651-1663", "issn-l": "2473-9529"}, "abstract": "Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.", "doi": "10.1182/bloodadvances.2018018903", "pmid": "29991496", "labels": {"Clinical Genomics Lund": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pii", "key": "bloodadvances.2018018903"}, {"db": "pmc", "key": "PMC6039664"}], "notes": [], "created": "2019-12-17T13:00:12.408Z", "modified": "2019-12-17T13:00:12.412Z"}], "created": "2019-09-16T11:35:19.748Z", "modified": "2020-11-27T13:14:10.389Z"}