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

Thorsson, Hanna LU ; Henningsson, Rasmus LU ; Puente-Moncada, Noelia LU ; Peña-Martínez, Pablo LU ; Sjöström, Ludvig LU ; Ågerstam, Helena LU ; Sandén, Carl LU ; Rissler, Marianne LU ; Castor, Anders LU orcid and Marquart, Hanne , et al. (2024) In Blood 144(13). p.1399-1411
Abstract

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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Single-Cell Analysis, Humans, Homeodomain Proteins/genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics, Genomics/methods, Animals, Mice, Child, Male, Female
in
Blood
volume
144
issue
13
pages
1399 - 1411
publisher
American Society of Hematology
external identifiers
  • pmid:38968149
  • scopus:85186122042
ISSN
1528-0020
DOI
10.1182/blood.2023021705
language
English
LU publication?
yes
additional info
© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
id
170f0088-3ca9-4892-8300-e740642c4193
date added to LUP
2024-09-30 08:45:25
date last changed
2024-10-01 04:00:42
@article{170f0088-3ca9-4892-8300-e740642c4193,
  abstract     = {{<p>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.</p>}},
  author       = {{Thorsson, Hanna and Henningsson, Rasmus and Puente-Moncada, Noelia and Peña-Martínez, Pablo and Sjöström, Ludvig and Ågerstam, Helena and Sandén, Carl and Rissler, Marianne and Castor, Anders and Marquart, Hanne and Modvig, Signe and Paulsson, Kajsa and Pronk, Cornelis Jan and Schmiegelow, Kjeld and Hyrenius-Wittsten, Axel and Orsmark-Pietras, Christina and Lilljebjörn, Henrik and Fioretos, Thoas}},
  issn         = {{1528-0020}},
  keywords     = {{Single-Cell Analysis; Humans; Homeodomain Proteins/genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics; Genomics/methods; Animals; Mice; Child; Male; Female}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{13}},
  pages        = {{1399--1411}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases}},
  url          = {{http://dx.doi.org/10.1182/blood.2023021705}},
  doi          = {{10.1182/blood.2023021705}},
  volume       = {{144}},
  year         = {{2024}},
}