title: Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.
abstract: 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.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Barrett
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Camille
authors.initials: C
authors.lastname: Malouf
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Chrysa
authors.initials: C
authors.lastname: Kapeni
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Wendi A
authors.initials: WA
authors.lastname: Bacon
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: George
authors.initials: G
authors.lastname: Giotopoulos
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Sten Eirik W
authors.initials: SEW
authors.lastname: Jacobsen
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. Electronic address: katrin.ottersbach@ed.ac.uk.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ottersbach
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal / Q000502:physiology*; D007938:Leukemia / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein