RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction.
The Mixed Lineage Leukemia (MLL) protein is an important epigenetic regulator required for the maintenance of gene activation during development. MLL chromosomal translocations produce novel fusion proteins that cause aggressive leukemias in humans. Individual MLL fusion proteins have distinct leukemic phenotypes even when expressed in the same cell type, but how this distinction is delineated on a molecular level is poorly understood. Here, we highlight a unique molecular mechanism whereby the RUNX1 gene is directly activated by MLL-AF4 and the RUNX1 protein interacts with the product of the reciprocal AF4-MLL translocation. These results support a mechanism of transformation whereby two oncogenic fusion proteins cooperate by activating a target gene and then modulating the function of its downstream product.
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Adam C
AC
Wilkinson
Erica
E
Ballabio
Huimin
H
Geng
Phillip
P
North
Marta
M
Tapia
Jon
J
Kerry
Debabrata
D
Biswas
Robert G
RG
Roeder
C David
CD
Allis
Ari
A
Melnick
Marella F T R
MF
de Bruijn
Thomas A
TA
Milne
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011379:Prognosis; D011485:Protein Binding / Q000235:genetics; D055550:Protein Stability; D015533:Transcriptional Activation; D014178:Translocation, Genetic / Q000235:genetics*; D016896:Treatment Outcome
D050676:Core Binding Factor Alpha 2 Subunit; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein