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


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Authors
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.

Description

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255


Funder: Newcastle NIHR-Biomedical Research Centre

Keywords
Article, /631/67/69, /631/67/1990/283, article
Journal Title
Nat Med
Conference Name
Journal ISSN
1078-8956
1546-170X
Volume Title
28
Publisher
Springer Science and Business Media LLC
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)