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Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Lookup NU author(s): Dr Laura JardineORCiD, Dr Simone WebbORCiD, Justin Engelbert, Dr Owen Williams, Professor Olaf Heidenreich, Dr Simon BomkenORCiD, Professor Muzlifah Haniffa

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

Pages: Epub ahead of print

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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Funding

Funder referenceFunder name
14-169
17-249
329
C27943/A12788
National Institute for Health Research Academic Clinical Lectureship
National Institute for Health Research-Great Ormond Street Hospital Biomedical Research Centre
KKL1142Kay Kendall Leukaemia Fund
Lister Institute of Preventative Medicine
MR/S021590/1Medical Research Council (MRC)
Newcastle National Institute for Health Research-Biomedical Research Centre
WT107931/Z/15/Z
WT110104/Z/15/Z
WT206194

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