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

Eleonora Khabirova, Laura Jardine, Tim H H Coorens, Simone Webb, Taryn D Treger, Justin Engelbert, Tarryn Porter, Elena Prigmore, Grace Collord, Alice Piapi, Sarah A Teichmann, Sarah Inglott, Owen Williams, Olaf Heidenreich, Matthew D Young, Karin Straathof, Simon Bomken, Jack Bartram, Muzlifah Haniffa, Sam Behjati

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)743-751
Number of pages9
JournalNature medicine
Volume28
Issue number4
DOIs
Publication statusPublished - Apr 2022

Keywords

  • Bone Marrow/metabolism
  • Child
  • Gene Rearrangement/genetics
  • Humans
  • Infant
  • Mutation/genetics
  • Myeloid-Lymphoid Leukemia Protein/genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Transcriptome/genetics

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