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  1. Article ; Online: Neutrophilic erythrophagocytosis in a child with paroxysmal cold hamoglobinuria.

    Pervaiz, Omer / Louka, Eleni / Willan, John

    EJHaem

    2022  Volume 3, Issue 4, Page(s) 1394–1395

    Language English
    Publishing date 2022-10-18
    Publishing country United States
    Document type Journal Article
    ISSN 2688-6146
    ISSN (online) 2688-6146
    DOI 10.1002/jha2.596
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: In utero origin of myelofibrosis presenting in adult monozygotic twins.

    Sousos, Nikolaos / Ní Leathlobhair, Máire / Simoglou Karali, Christina / Louka, Eleni / Bienz, Nicola / Royston, Daniel / Clark, Sally-Ann / Hamblin, Angela / Howard, Kieran / Mathews, Vikram / George, Biju / Roy, Anindita / Psaila, Bethan / Wedge, David C / Mead, Adam J

    Nature medicine

    2022  Volume 28, Issue 6, Page(s) 1207–1211

    Abstract: The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive ... ...

    Abstract The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.
    MeSH term(s) Calreticulin ; Humans ; Janus Kinase 2/genetics ; Mutation/genetics ; Myeloproliferative Disorders/genetics ; Primary Myelofibrosis/genetics ; Twins, Monozygotic/genetics
    Chemical Substances Calreticulin ; Janus Kinase 2 (EC 2.7.10.2)
    Language English
    Publishing date 2022-05-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-022-01793-4
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    Zs.A 4212: Show issues Location:
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  3. Article ; Online: Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution.

    Rodriguez-Meira, Alba / Norfo, Ruggiero / Wen, Sean / Chédeville, Agathe L / Rahman, Haseeb / O'Sullivan, Jennifer / Wang, Guanlin / Louka, Eleni / Kretzschmar, Warren W / Paterson, Aimee / Brierley, Charlotte / Martin, Jean-Edouard / Demeule, Caroline / Bashton, Matthew / Sousos, Nikolaos / Moralli, Daniela / Subha Meem, Lamia / Carrelha, Joana / Wu, Bishan /
    Hamblin, Angela / Guermouche, Helene / Pasquier, Florence / Marzac, Christophe / Girodon, François / Vainchenker, William / Drummond, Mark / Harrison, Claire / Chapman, J Ross / Plo, Isabelle / Jacobsen, Sten Eirik W / Psaila, Bethan / Thongjuea, Supat / Antony-Debré, Iléana / Mead, Adam J

    Nature genetics

    2023  Volume 55, Issue 9, Page(s) 1531–1541

    Abstract: Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution ... ...

    Abstract Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.
    MeSH term(s) Humans ; Multiomics ; Neoplasm Proteins ; Inflammation/genetics ; Alleles ; Leukemia/genetics ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Neoplasm Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2023-09-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-023-01480-1
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    Zs.A 3613: Show issues Location:
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    Zs.MG 46: Show issues

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  4. Article: Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing

    Rodriguez-Meira, Alba / Buck, Gemma / Clark, Sally-Ann / Povinelli, Benjamin J / Alcolea, Veronica / Louka, Eleni / McGowan, Simon / Hamblin, Angela / Sousos, Nikolaos / Barkas, Nikolaos / Giustacchini, Alice / Psaila, Bethan / Jacobsen, Sten Eirik W / Thongjuea, Supat / Mead, Adam J

    Molecular cell. 2019 Jan. 07,

    2019  

    Abstract: Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for resolving transcriptional heterogeneity. However, its application to studying cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the ... ...

    Abstract Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for resolving transcriptional heterogeneity. However, its application to studying cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the vast majority of cells; this lack of coverage prevents the correlation of genetic and transcriptional readouts from the same single cell. To overcome this, we developed TARGET-seq, a method for the high-sensitivity detection of multiple mutations within single cells from both genomic and coding DNA, in parallel with unbiased whole-transcriptome analysis. Applying TARGET-seq to 4,559 single cells, we demonstrate how this technique uniquely resolves transcriptional and genetic tumor heterogeneity in myeloproliferative neoplasms (MPN) stem and progenitor cells, providing insights into deregulated pathways of mutant and non-mutant cells. TARGET-seq is a powerful tool for resolving the molecular signatures of genetically distinct subclones of cancer cells.
    Keywords DNA ; genomics ; mutants ; mutation ; mutational analysis ; neoplasm cells ; neoplasms ; stem cells ; tissues ; transcription (genetics)
    Language English
    Dates of publication 2019-0107
    Publishing place Elsevier Inc.
    Document type Article
    Note Pre-press version
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2019.01.009
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  5. Article ; Online: Carfilzomib therapy for relapsed myeloma: results of a UK multicentre experience.

    Djebbari, Faouzi / Hubenov, Huben / Neelakantan, Pratap / Wolf, Julia / Offer, Mark / Khera, Akhil / Louka, Eleni / Vallance, Grant / Kothari, Jaimal / Moore, Sally / Ramasamy, Karthik

    British journal of haematology

    2019  Volume 188, Issue 4, Page(s) e57–e60

    MeSH term(s) Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma/blood ; Multiple Myeloma/drug therapy ; Oligopeptides/administration & dosage ; Oligopeptides/adverse effects ; Recurrence ; Retrospective Studies ; United Kingdom
    Chemical Substances Oligopeptides ; carfilzomib (72X6E3J5AR)
    Language English
    Publishing date 2019-12-02
    Publishing country England
    Document type Clinical Trial ; Letter ; Multicenter Study
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/bjh.16324
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    Uh III Zs.182: Show issues Location:
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  6. Article ; Online: Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia.

    Louka, Eleni / Povinelli, Benjamin / Rodriguez-Meira, Alba / Buck, Gemma / Wen, Wei Xiong / Wang, Guanlin / Sousos, Nikolaos / Ashley, Neil / Hamblin, Angela / Booth, Christopher A G / Roy, Anindita / Elliott, Natalina / Iskander, Deena / de la Fuente, Josu / Fordham, Nicholas / O'Byrne, Sorcha / Inglott, Sarah / Norfo, Ruggiero / Salio, Mariolina /
    Thongjuea, Supat / Rao, Anupama / Roberts, Irene / Mead, Adam J

    The Journal of experimental medicine

    2021  Volume 218, Issue 2

    Abstract: Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA ...

    Abstract Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.
    MeSH term(s) Animals ; Biomarkers, Tumor/genetics ; Cell Line ; Female ; Hematopoietic Stem Cells/pathology ; Humans ; Leukemia, Myelomonocytic, Juvenile/genetics ; Leukemia, Myelomonocytic, Juvenile/pathology ; Male ; Mice ; Mutation/genetics ; Neoplastic Stem Cells/pathology ; Signal Transduction/genetics ; Up-Regulation/genetics
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2021-01-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20180853
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.107: Show issues Location:
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  7. Article ; Online: Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing.

    Rodriguez-Meira, Alba / Buck, Gemma / Clark, Sally-Ann / Povinelli, Benjamin J / Alcolea, Veronica / Louka, Eleni / McGowan, Simon / Hamblin, Angela / Sousos, Nikolaos / Barkas, Nikolaos / Giustacchini, Alice / Psaila, Bethan / Jacobsen, Sten Eirik W / Thongjuea, Supat / Mead, Adam J

    Molecular cell

    2019  Volume 73, Issue 6, Page(s) 1292–1305.e8

    Abstract: Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for resolving transcriptional heterogeneity. However, its application to studying cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the ... ...

    Abstract Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for resolving transcriptional heterogeneity. However, its application to studying cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the vast majority of cells; this lack of coverage prevents the correlation of genetic and transcriptional readouts from the same single cell. To overcome this, we developed TARGET-seq, a method for the high-sensitivity detection of multiple mutations within single cells from both genomic and coding DNA, in parallel with unbiased whole-transcriptome analysis. Applying TARGET-seq to 4,559 single cells, we demonstrate how this technique uniquely resolves transcriptional and genetic tumor heterogeneity in myeloproliferative neoplasms (MPN) stem and progenitor cells, providing insights into deregulated pathways of mutant and non-mutant cells. TARGET-seq is a powerful tool for resolving the molecular signatures of genetically distinct subclones of cancer cells.
    MeSH term(s) Biomarkers, Tumor/genetics ; DNA Mutational Analysis/methods ; Genetic Heterogeneity ; High-Throughput Nucleotide Sequencing ; Humans ; Jurkat Cells ; K562 Cells ; Leukemia/genetics ; Mutation ; Reproducibility of Results ; Schizosaccharomyces/genetics ; Sequence Analysis, RNA ; Single-Cell Analysis
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2019-02-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2019.01.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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