Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C.
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 mixed-lineage 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.
Schwieger
Maike
M
Heinrich-Pette-Institute, Hamburg, Germany.
Schüler
Andrea
A
Forster
Martin
M
Engelmann
Afra
A
Arnold
Michael A
MA
Delwel
Ruud
R
Valk
Peter J
PJ
Löhler
Jürgen
J
Slany
Robert K
RK
Olson
Eric N
EN
Stocking
Carol
C
D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000502:physiology; D009052:Leukemia Virus, Murine / Q000502:physiology; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D000099185:Interferon Regulatory Factor-8
D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D064326:MEF2 Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D018006:Myogenic Regulatory Factors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C578041:Mef2c protein, mouse; C493508:Mllt1 protein, mouse