Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development

• Mll-AF4 confers enhanced B cell potential and causes an expansion of pro-B cells
• Mll-AF4 increases self-renewal potential
• Mll-AF4 exerts its effects in a restricted developmental window
• The LMPP is a potential cell of origin for Mll-AF4-associated disease

SummaryMLL-AF4+ infant B cell acute lymphoblastic leukemia is characterized by an early onset and dismal survival. It initiates before birth, and very little is known about the early stages of the disease’s development. Using a conditional Mll-AF4-expressing mouse model in which fusion expression is targeted to the earliest definitive hematopoietic cells generated in the mouse embryo, we demonstrate that Mll-AF4 imparts enhanced B lymphoid potential and increases repopulation and self-renewal capacity during a putative pre-leukemic state. This occurs between embryonic days 12 and 14 and manifests itself most strongly in the lymphoid-primed multipotent progenitor population, thus pointing to a window of opportunity and a potential cell of origin. However, this state alone is insufficient to generate disease, with the mice succumbing to B cell lymphomas only after a long latency. Future analysis of the molecular details of this pre-leukemic state will shed light on additional events required for progression to acute leukemia.

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