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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases

Author

  • Hanna Thorsson
  • Rasmus Henningsson
  • Noelia Puente-Moncada
  • Pablo Peña-Martínez
  • Ludvig Sjöström
  • Helena Ågerstam
  • Carl Sandén
  • Marianne Rissler
  • Anders Castor
  • Hanne Marquart
  • Signe Modvig
  • Kajsa Paulsson
  • Cornelis Jan Pronk
  • Kjeld Schmiegelow
  • Axel Hyrenius-Wittsten
  • Christina Orsmark-Pietras
  • Henrik Lilljebjörn
  • Thoas Fioretos
Show all

Summary, in English

B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs belonging to the BCR::ABL1+, ETV6::RUNX1+, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Although the BCR::ABL1+, ETV6::RUNX1+, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed not only multilineage priming toward nonhematopoietic cells, myeloid, and T-cell lineages, but also an activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of DUX4-r blasts with aberrant expression of myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype, with implications for the understanding of ALL biology and new therapeutic strategies.

Department/s

  • LUCC: Lund University Cancer Centre
  • Division of Clinical Genetics
  • Translational Genomic and Functional Studies of Leukemia
  • Targeted therapies in leukemia
  • Aneuploidy in cancer
  • Synthetic Immunology
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy
  • LTH Profile Area: Engineering Health

Publishing year

2024-09-26

Language

English

Pages

1399-1411

Publication/Series

Blood

Volume

144

Issue

13

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Cancer and Oncology
  • Medical Genetics
  • Hematology

Keywords

  • Single-Cell Analysis
  • Humans
  • Homeodomain Proteins/genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Genomics/methods
  • Animals
  • Mice
  • Child
  • Male
  • Female

Status

Published

Research group

  • Translational Genomic and Functional Studies of Leukemia
  • Targeted therapies in leukemia
  • Aneuploidy in cancer
  • Synthetic Immunology
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy

ISBN/ISSN/Other

  • ISSN: 1528-0020