MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele.
Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, 19104, USA.
Austin T
AT
Thiel
Peter
P
Blessington
Tao
T
Zou
Danielle
D
Feather
Xinjiang
X
Wu
Jizhou
J
Yan
Hui
H
Zhang
Zuguo
Z
Liu
Patricia
P
Ernst
Gary A
GA
Koretzky
Xianxin
X
Hua
D000483:Alleles; D000818:Animals; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014178:Translocation, Genetic
D006657:Histones; D018398:Homeodomain Proteins; C105373:MEN1 protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein