Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis.
MLL1 fusion proteins activate HoxA9 gene expression and cause aggressive leukemias that respond poorly to treatment, but how they recognize and stably bind to HoxA9 is not clearly understood. In a systematic analysis of MLL1 domain recruitment activity, we identified an essential MLL1 recruitment domain that includes the CXXC domain and PHD fingers and is controlled by direct interactions with the PAF elongation complex and H3K4Me2/3. MLL1 fusion proteins lack the PHD fingers and require prebinding of a wild-type MLL1 complex and CXXC domain recognition of DNA for stable HoxA9 association. Together, these results suggest that specific recruitment of MLL1 requires multiple interactions and is a precondition for stable recruitment of MLL1 fusion proteins to HoxA9 in leukemogenesis. Since wild-type MLL1 and oncogenic MLL1 fusion proteins have overlapping yet distinct recruitment mechanisms, this creates a window of opportunity that could be exploited for the development of targeted therapies.
Milne
Thomas A
TA
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
Kim
Jaehoon
J
Wang
Gang G
GG
Stadler
Sonja C
SC
Basrur
Venkatesha
V
Whitcomb
Sarah J
SJ
Wang
Zhanxin
Z
Ruthenburg
Alexander J
AJ
Elenitoba-Johnson
Kojo S J
KS
Roeder
Robert G
RG
Allis
C David
CD
D000818:Animals; D002460:Cell Line; D056426:Genetic Loci; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014157:Transcription Factors
D018398:Homeodomain Proteins; C551356:MLL-AF9 fusion protein, mouse; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C501972:PAF1 protein, human; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse