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<p>Infant Acute Lymphoblastic Leukemia (ALL) driven by the <i>KMT2A::AFF1</i> onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates <i>in utero</i>, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine <i>KMT2A::AFF1</i> model, that provides key insights into <i>KMT2A::AFF1</i> 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 <i>KMT2A::AFF1</i> 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 <i>Hmga2</i>, 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月11日

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  • Ariana S. Calderón,
  • Roshanak Ghazanfari,
  • Zahra Masoumi,
  • Shabnam Kharazi,
  • Sara Palo,
  • Stefan Lang,
  • Kristijonas Žemaitis,
  • Mohamed Eldeeb,
  • Agatheeswaran Subramaniam,
  • Shamit Soneji,
  • Ronald W. Stam,
  • David Bryder,
  • Charlotta Böiers

摘要

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.