Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation

Cell Rep. 2014 Nov 20;9(4):1246-55. doi: 10.1016/j.celrep.2014.10.036. Epub 2014 Nov 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Differentiation / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology*
  • Cytoprotection* / drug effects
  • Disease Models, Animal
  • Doxycycline / pharmacology
  • Gene Expression Regulation, Leukemic / drug effects
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Progenitor Cells / pathology
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Oncogene Proteins, Fusion / metabolism*
  • Reproducibility of Results
  • Transcription, Genetic / drug effects


  • MLL-ENL oncoprotein, human
  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Doxycycline

Associated data

  • GEO/GSE62734