Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia.
Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.
Guenther
Matthew G
MG
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Lawton
Lee N
LN
Rozovskaia
Tatiana
T
Frampton
Garrett M
GM
Levine
Stuart S
SS
Volkert
Thomas L
TL
Croce
Carlo M
CM
Nakamura
Tatsuya
T
Canaani
Eli
E
Young
Richard A
RA
D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002843:Chromatin / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D011993:Recombinant Fusion Proteins; D051788:Myeloid-Lymphoid Leukemia Protein