Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C
Schwieger M, Schueler A, Forster M, Engelmann A, Arnold MA, Delwel R, Valk PJ, Loehler J, Slany R, Olson EN, Stocking C (2009)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2009
Journal
Book Volume: 114
Pages Range: 2476-2488
Journal Issue: 12
DOI: 10.1182/blood-2008-05-158196
Abstract
Acute myelogenous leukemia is driven by leukemic stem cells (LSCs) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSCs in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Among the targeted genes, we identified Mef2c, encoding a MCM1-agamous-deficiens-serum response factor transcription factor, and confirmed that overexpression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be up-regulated in the mixedlineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in acute myelogenous leukemia 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 or maintenance of LSCs 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, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype. © 2009 by The American Society of Hematology.
Authors with CRIS profile
Involved external institutions
Heinrich-Pette-Institut (HPI), Leibniz-Institut für Experimentelle Virologie / Heinrich Pette Institute – Leibniz Institute for Experimental Virology
Germany (DE)
University of Texas Southwestern Medical Center (UT Southwestern)
United States (USA) (US)
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Netherlands (NL)
Germany (DE)
University of Texas Southwestern Medical Center (UT Southwestern)
United States (USA) (US)
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Netherlands (NL)
How to cite
APA:
Schwieger, M., Schueler, A., Forster, M., Engelmann, A., Arnold, M.A., Delwel, R.,... Stocking, C. (2009). Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. Blood, 114(12), 2476-2488. https://doi.org/10.1182/blood-2008-05-158196
MLA:
Schwieger, Maike, et al. "Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C." Blood 114.12 (2009): 2476-2488.
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