Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

Maike Schwieger, Andrea Schüler, Martin Forster, Afra Engelmann, Michael A. Arnold, Ruud Delwel, Peter J. Valk, Jürgen Löhler, Robert K. Slany, Eric N. Olson, Carol Stocking

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2476-2488
Number of pages13
JournalBlood
Volume114
Issue number12
DOIs
StatePublished - 2009

Fingerprint

Leukemia
Genes
Stem cells
Gene encoding
Interferons
Stem Cells
Serum Response Factor
Acute Myeloid Leukemia
Mutagenesis
Matrix Metalloproteinases
Chemokines
Tumors
Transcription Factors
Fusion reactions
Chemokine Receptors
Cells
Ligands
Up-Regulation
Maintenance
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Schwieger, M., Schüler, 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

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. / Schwieger, Maike; Schüler, Andrea; Forster, Martin; Engelmann, Afra; Arnold, Michael A.; Delwel, Ruud; Valk, Peter J.; Löhler, Jürgen; Slany, Robert K.; Olson, Eric N.; Stocking, Carol.

In: Blood, Vol. 114, No. 12, 2009, p. 2476-2488.

Research output: Contribution to journalArticle

Schwieger, M, Schüler, A, Forster, M, Engelmann, A, Arnold, MA, Delwel, R, Valk, PJ, Löhler, J, Slany, RK, Olson, EN & Stocking, C 2009, 'Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C', Blood, vol. 114, no. 12, pp. 2476-2488. https://doi.org/10.1182/blood-2008-05-158196
Schwieger M, Schüler A, Forster M, Engelmann A, Arnold MA, Delwel R et al. Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. Blood. 2009;114(12):2476-2488. https://doi.org/10.1182/blood-2008-05-158196
Schwieger, Maike ; Schüler, Andrea ; Forster, Martin ; Engelmann, Afra ; Arnold, Michael A. ; Delwel, Ruud ; Valk, Peter J. ; Löhler, Jürgen ; Slany, Robert K. ; Olson, Eric N. ; Stocking, Carol. / Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. In: Blood. 2009 ; Vol. 114, No. 12. pp. 2476-2488.
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