|
|
Blood, 17 September 2009, Vol. 114, No. 12, pp. 2476-2488.
Prepublished online as a Blood First Edition Paper on July 22, 2009July 7, 2009; DOI 10.1182/blood-2008-05-158196.
 Previous Article | Next Article 
Submitted May 21, 2008
Accepted June 14, 2009
Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C
Maike Schwieger, Andrea Schuler, Martin Forster, Afra Engelmann, Michael A. Arnold, Ruud Delwel, Peter J. Valk, Jurgen Lohler, Robert K. Slany, Eric N. Olson, and Carol Stocking*
Heinrich-Pette-Institute, Hamburg, Germany
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States
Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
Department of Genetics, University of Erlangen, Erlangen, Germany
* Corresponding author; email: stocking{at}hpi.uni-hamburg.de.
Acute myelogenous leukemia (AML) is driven by leukemic stem cells (LSC) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSC in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Amongst the targeted genes, we identified Mef2c, encoding a MADS transcription factor, and confirmed that over-expression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be upregulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in AML patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment nor maintenance of LSC generated in vitro by MLL/ENL fusion proteins - however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus an early event in LSC generation may be responsible for the aggressive nature of this leukemia subtype.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
