Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
03
08
2021
accepted:
27
01
2022
pubmed:
16
3
2022
medline:
22
4
2022
entrez:
15
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35288693
doi: 10.1038/s41591-022-01720-7
pii: 10.1038/s41591-022-01720-7
pmc: PMC9018413
mid: EMS144370
doi:
Substances chimiques
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
743-751Subventions
Organisme : Cancer Research UK
ID : A12788
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110104
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107931
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021590/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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