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

Calderón AS, Ghazanfari R, Masoumi Z, Kharazi S, Palo S, Lang S, Žemaitis K, Eldeeb M, Subramaniam A, Soneji S, Stam RW, Bryder D, Böiers C

Leukemia 39 (9) 2099-2111 [2025-09-00; online 2025-07-11]

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.

Clinical Genomics Lund [Service]

PubMed 40646135

DOI 10.1038/s41375-025-02665-9

Crossref 10.1038/s41375-025-02665-9

pmc: PMC12380613
pii: 10.1038/s41375-025-02665-9