Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells.
HCC is a molecularly heterogeneous disease. The present study by Takeda et al. (4) indicates that a subclass of patients with activated HGF-MET signaling might also display induction of MLL expression. This induction stabilizes the MLL-ETS2 complex and increases H3K4me3. Activation of this signaling cascade confers invasive tumor growth of HCC cells and seeding of distant metastasis via MMP1 and MMP3 upregulation, which might explain the poor outcome associated with MET activation. Therefore, this newly described engagement of HGF-MET and MLL might provide a promising approach for selection of HCC patients most likely to benefit from targeted therapies with MLL, taspase-1, or MET inhibitors and ultimately improve patient survival.