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Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state

Calderón, Ariana S. LU ; Ghazanfari, Roshanak LU ; Masoumi, Zahra LU orcid ; Kharazi, Shabnam LU ; Palo, Sara LU ; Lang, Stefan LU orcid ; Žemaitis, Kristijonas LU ; Eldeeb, Mohamed LU ; Subramaniam, Agatheeswaran LU and Soneji, Shamit LU , et al. (2025) In Leukemia 39(9). p.2099-2111
Abstract

Infant Acute Lymphoblastic Leukemia (ALL) driven by the KMT2A::AFF1 onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates in utero, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine KMT2A::AFF1 model, that provides key insights into KMT2A::AFF1 pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24+PreProB subset expanded exclusively within the... (More)

Infant Acute Lymphoblastic Leukemia (ALL) driven by the KMT2A::AFF1 onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates in utero, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine KMT2A::AFF1 model, that provides key insights into KMT2A::AFF1 pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24+PreProB subset expanded exclusively within the KMT2A::AFF1 embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24+PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of Hmga2, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease. (Figure presented.)

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Leukemia
volume
39
issue
9
pages
2099 - 2111
publisher
Nature Publishing Group
external identifiers
  • pmid:40646135
  • scopus:105010622804
ISSN
0887-6924
DOI
10.1038/s41375-025-02665-9
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
d7148268-68b3-43ff-85fd-d4bfa2d5920f
date added to LUP
2025-09-19 16:12:23
date last changed
2025-10-03 18:09:49
@article{d7148268-68b3-43ff-85fd-d4bfa2d5920f,
  abstract     = {{<p>Infant Acute Lymphoblastic Leukemia (ALL) driven by the KMT2A::AFF1 onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates in utero, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine KMT2A::AFF1 model, that provides key insights into KMT2A::AFF1 pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24<sup>+</sup>PreProB subset expanded exclusively within the KMT2A::AFF1 embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24<sup>+</sup>PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of Hmga2, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease. (Figure presented.)</p>}},
  author       = {{Calderón, Ariana S. and Ghazanfari, Roshanak and Masoumi, Zahra and Kharazi, Shabnam and Palo, Sara and Lang, Stefan and Žemaitis, Kristijonas and Eldeeb, Mohamed and Subramaniam, Agatheeswaran and Soneji, Shamit and Stam, Ronald W. and Bryder, David and Böiers, Charlotta}},
  issn         = {{0887-6924}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2099--2111}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Leukemia}},
  title        = {{Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state}},
  url          = {{http://dx.doi.org/10.1038/s41375-025-02665-9}},
  doi          = {{10.1038/s41375-025-02665-9}},
  volume       = {{39}},
  year         = {{2025}},
}