Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development
Neil A. Barrett,
Camille Malouf,
Chrysa Kapeni,
Wendi A. Bacon,
George Giotopoulos,
Sten Eirik W. Jacobsen,
Brian J. Huntly,
Katrin Ottersbach
Affiliations
Neil A. Barrett
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
Camille Malouf
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
Chrysa Kapeni
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
Wendi A. Bacon
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
George Giotopoulos
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
Sten Eirik W. Jacobsen
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Brian J. Huntly
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
Katrin Ottersbach
Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK
MLL-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.
