Abstract
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.
Highlights
While many pediatric leukemias have enjoyed significant advances in treatment in recent years that dramatically increase long-term survival rates, infant leukemia associated with the MLL-AF4 fusion continues to have a dismal prognosis
Mll1 Is Widely Expressed in the Developing Hematopoietic System Since the expression of the Mll-AF4 fusion gene is controlled by the regulatory elements of the endogenous murine Mll1 gene, we analyzed Mll1 expression in mouse embryonic and fetal hematopoietic tissues, as well as sorted cell populations, by qPCR to narrow down the potential target cells for transformation
The aorta-gonads-mesonephros (AGM) region is the first location in which adult-repopulating hematopoietic stem cells (HSCs) are detected, starting from embryonic day (E)10.5 (Medvinsky and Dzierzak, 1996; Mu€ller et al, 1994)
Summary
While many pediatric leukemias have enjoyed significant advances in treatment in recent years that dramatically increase long-term survival rates, infant leukemia associated with the MLL-AF4 fusion continues to have a dismal prognosis. The in utero origin of MLL-AF4-associated infant leukemia poses a major challenge to the study of this malignancy. For this reason a faithful in vitro or animal model is required to allow analysis of the early changes in the blood system that lead to leukemia development. Such models are a prerequisite for elucidating the pathogenesis of the disease, as well as testing treatments. While transduction of mouse LinSca1+ cells with MLL-AF4 (albeit at very low transduction efficiencies) had no effect, transduction with the reciprocal fusion AF4-MLL produced pro-B ALL with a long latency (Bursen et al, 2010)
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