Global Loss of Imprinting in Embryonic Stem Cells Leads to Widespread Tumorigenesis in Adult Mice
T.M. Holm, L. Jackson-Grusby, T. Bambrick, Y. Yamada, W.M. Rideout 3rd, R. Jaenisch
The Whitehead Institute/MIT, 9 Cambridge Center, Cambridge, MA 02142, USA
Imprinting is a mammalian adaptation whereby subsets of genes are
differentially expressed depending on their parental origin; this
monoallelic expression is maintained by DNA methylation. Loss of
imprinting (LOI) is a common feature of many human tumors, yet whether
LOI directly promotes tumorigenesis or is merely a consequence of
epigenetic deregulation in transformed cells is unclear. To directly
examine the function of LOI in tumorigenesis, we developed a model for
LOI using conditional inactivation and reactivation of the DNA
methyltransferase Dnmt1 to generate imprint-free mouse embryonic stem
cells (IF-ES cells). IF- embryonic fibroblasts (IF-MEFs) derived from
these ES cells display an increased growth rate, cellular immortality,
resistance to growth inhibition by TGFb and form tumors when injected
into SCID mice. Somatic contribution of IF-ES cells in chimeric animals
leads to tumor formation by 12 months of age, causing hepatocellular
carcinoma, intestinal adenomas, and a range of other primary cancers
derived from the IF-ES cells. Our data are consistent with global LOI
in embryonic stem cells having a causal role in tumor formation in
adults. This finding demonstrates the importance of imprinting as a
tumor suppressor mechanism and identifies a pathway by which
immortality conferred by LOI lowers the threshold for transformation.
Key words:
Cancer, Stem cells, Loss of Imprinting
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