title: Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.
abstract: Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development.
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden.
authors.forename: Amol
authors.initials: A
authors.lastname: Ugale
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Gudmundur L
authors.initials: GL
authors.lastname: Norddahl
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Wahlestedt
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Säwén
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden.
authors.forename: Pekka
authors.initials: P
authors.lastname: Jaako
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden; Lund Stem Cell Center, Biomedical Center B10, Klinikgatan 26, 221 84 Lund, Sweden.
authors.forename: Cornelis Jan
authors.initials: CJ
authors.lastname: Pronk
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Biomedical Center A12, Lund University, 221 84 Lund, Sweden; Lund Stem Cell Center, Biomedical Center B10, Klinikgatan 26, 221 84 Lund, Sweden.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Biomedical Center A12, Lund University, 221 84 Lund, Sweden; Lund Stem Cell Center, Biomedical Center B10, Klinikgatan 26, 221 84 Lund, Sweden.
authors.forename: Jörg
authors.initials: J
authors.lastname: Cammenga
authors.affiliation: Immunology Section, Department of Experimental Medical Science, Biomedical Center D14, Lund University, Klinikgatan 32, 221 84 Lund, Sweden; Lund Stem Cell Center, Biomedical Center B10, Klinikgatan 26, 221 84 Lund, Sweden. Electronic address: david.bryder@med.lu.se.
authors.forename: David
authors.initials: D
authors.lastname: Bryder
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D015203:Reproducibility of Results; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D004318:Doxycycline