@article{6c79cb3610b84aa587f418d3dc9a5432,
title = "Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia",
abstract = "KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.",
keywords = "Bone Marrow/metabolism, Child, Gene Rearrangement/genetics, Humans, Infant, Mutation/genetics, Myeloid-Lymphoid Leukemia Protein/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics, Transcriptome/genetics",
author = "Eleonora Khabirova and Laura Jardine and Coorens, {Tim H H} and Simone Webb and Treger, {Taryn D} and Justin Engelbert and Tarryn Porter and Elena Prigmore and Grace Collord and Alice Piapi and Teichmann, {Sarah A} and Sarah Inglott and Owen Williams and Olaf Heidenreich and Young, {Matthew D} and Karin Straathof and Simon Bomken and Jack Bartram and Muzlifah Haniffa and Sam Behjati",
note = "Funding Information: We thank I. Roberts and A. Roy, both from the University of Oxford, and A. Maartens (science writer at the Wellcome Sanger Institute) for critical review of the manuscript. We thank A. Filby and his team at the Flow Cytometry Core Facility, Newcastle University, for their advice and support. Samples were contributed by the SIHMDS at Great Ormond Street Hospital and by the Newcastle Biobank http://www.ncl.ac.uk/biobanks/. We are indebted to patients and their families for participating in our research. This study was funded by Wellcome Trust grants WT206194 (Wellcome Sanger Institute), WT110104/Z/15/Z (S. Behjati) and WT107931/Z/15/Z (M.H.); the Lister Institute of Preventative Medicine (M.H.); the Newcastle National Institute for Health Research-Biomedical Research Centre (M.H. and L.J.); the National Institute for Health Research Academic Clinical Lectureship (L.J.); Medical Research Council clinician scientist fellowship MR/S021590/1 (S. Bomken); CRUK program grant C27943/A12788 (O.H.); the Kay Kendall Leukaemia Fund (KKL1142) (O.H.); Kika program grant 329 (O.H.); Children with Cancer UK grant 14-169,17-249; and the National Institute for Health Research-Great Ormond Street Hospital Biomedical Research Centre (O.W.). Funding Information: We thank I. Roberts and A. Roy, both from the University of Oxford, and A. Maartens (science writer at the Wellcome Sanger Institute) for critical review of the manuscript. We thank A. Filby and his team at the Flow Cytometry Core Facility, Newcastle University, for their advice and support. Samples were contributed by the SIHMDS at Great Ormond Street Hospital and by the Newcastle Biobank http://www.ncl.ac.uk/biobanks/ . We are indebted to patients and their families for participating in our research. This study was funded by Wellcome Trust grants WT206194 (Wellcome Sanger Institute), WT110104/Z/15/Z (S. Behjati) and WT107931/Z/15/Z (M.H.); the Lister Institute of Preventative Medicine (M.H.); the Newcastle National Institute for Health Research-Biomedical Research Centre (M.H. and L.J.); the National Institute for Health Research Academic Clinical Lectureship (L.J.); Medical Research Council clinician scientist fellowship MR/S021590/1 (S. Bomken); CRUK program grant C27943/A12788 (O.H.); the Kay Kendall Leukaemia Fund (KKL1142) (O.H.); Kika program grant 329 (O.H.); Children with Cancer UK grant 14-169,17-249; and the National Institute for Health Research-Great Ormond Street Hospital Biomedical Research Centre (O.W.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = apr,
doi = "10.1038/s41591-022-01720-7",
language = "English",
volume = "28",
pages = "743--751",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}