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Lookup NU author(s): Dr Laura JardineORCiD, Dr Simone WebbORCiD, Justin Engelbert, Dr Owen Williams, Professor Olaf Heidenreich, Dr Simon BomkenORCiD, Professor Muzlifah Haniffa
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022, The Author(s). 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.
Author(s): Khabirova E, Jardine L, Coorens THH, Webb S, Treger TD, Engelbert J, Porter T, Prigmore E, Collord G, Piapi A, Teichmann SA, Inglott S, Williams O, Heidenreich O, Young MD, Straathof K, Bomken S, Bartram J, Haniffa M, Behjati S
Publication type: Article
Publication status: Published
Journal: Nature Medicine
Year: 2022
Volume: 28
Pages: 743-751
Print publication date: 01/04/2022
Online publication date: 14/03/2022
Acceptance date: 27/01/2022
Date deposited: 29/03/2022
ISSN (print): 1078-8956
ISSN (electronic): 1546-170X
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41591-022-01720-7
DOI: 10.1038/s41591-022-01720-7
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