Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.
Authors
Treger, Taryn D
Engelbert, Justin
Porter, Tarryn
Collord, Grace
Inglott, Sarah
Straathof, Karin
Publication Date
2022-04Journal Title
Nat Med
ISSN
1078-8956
Publisher
Springer Science and Business Media LLC
Volume
28
Issue
4
Pages
743-751
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Khabirova, E., Jardine, L., Coorens, T. H., Webb, S., Treger, T. D., Engelbert, J., Porter, T., et al. (2022). Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.. Nat Med, 28 (4), 743-751. https://doi.org/10.1038/s41591-022-01720-7
Description
Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255
Funder: Newcastle NIHR-Biomedical Research Centre
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
Article, /631/67/69, /631/67/1990/283, article
Sponsorship
Wellcome Trust (Wellcome) (WT206194, WT107931/Z/15/Z)
Wellcome Trust (Wellcome) (WT110104/Z/15/Z)
DH | National Institute for Health Research (NIHR) (Academic Clinical Lectureship)
CHILDREN with CANCER UK (14-169, 17-249)
Cancer Research UK (CRUK) (C27943/A12788)
Kay Kendall Leukaemia Fund (KKLF) (KKL1142)
Stichting Kinderen Kankervrij (KiKa) (329)
RCUK | Medical Research Council (MRC) (MR/S021590/1)
Identifiers
s41591-022-01720-7, 1720
External DOI: https://doi.org/10.1038/s41591-022-01720-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336266
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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