The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPα and differentiation in MLL-AF9 leukemia.

Trithorax and polycomb group proteins antagonistically regulate the transcription of many genes, and cancer can result from the disruption of this regulation. Deregulation of trithorax function occurs through chromosomal translocations involving the trithorax gene MLL, leading to the expression of MLL fusion proteins and acute leukemia. It is poorly understood how MLL fusion proteins block differentiation, a hallmark of leukemogenesis.

Menin as a hub controlling mixed lineage leukemia.

Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs, and other partners such as the chromatin-associated protein LEDGF and the transcription factor C-Myb to promote leukemogenesis.

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.