Histone methyltransferase PRDM16 in tumor suppression

PRDM16 is highly enriched in adult stem cells and plays a crucial role in multiple developmental processes. Here we demonstrate that PRDM16 is a histone H3K4 methyltransferase and this activity is essential for PRDM16 to function as a tumor suppressor. We show that PRDM16, through its regulation of transcription factor GFI1b, antagonizes the functions of MLL fusion proteins by repressing HOXA gene expression and therefore, specifically suppresses the transformation capability of MLL-AF9, MLL-AF6 and MLL-ENL. Furthermore, overexpression of PRDM16, but not the inactive PRDM16 mutant, blocks MLL mediated leukemogenesis while PRDM16 depletion significantly shortens the disease latency in vivo. We also show that PRDM16 activity is dynamically required at the pre-leukemic stage, but not in fully transformed leukemia, depicting a little known sequence of events necessary for clonal expansion during cancer evolution. Given the importance of PRDM16 and the loss of PRDM16 methyltransferase activity in an array of human malignancies, our findings provide broad insights for PRDM16-dependent physiological and pathological processes. Overall design: Compare MLL-AF9+PRDM16 contransduction with MLL-AF9+PRDM16mut cotransduction; Compare E2A-HLF+PRDM16 contransduction with E2A-HLF+PRDM16mut cotransduction; Compare MLL-AF9 stable leukemia cell +PRDM16 with MLL-AF9 stable leukemia+PRDM16mut; Two replicates in each condition