UC San Diego

Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have divided MB into four molecular subgroups: WNT, SHH, Group 3, and Group 4. While WNT and SHH tumors have relatively favorable prognoses, Group 3 tumors (characterized by amplification or overexpression of the MYC oncogene) are frequently fatal. The first mouse models of Group 3 MB combine Myc overexpression and p53 loss of function, but they do not precisely recapitulate the disease genetics, as human Group 3 tumors rarely exhibit mutation or loss of p53. Thus, the goal of my research has been to identify secondary hits that can cooperate with MYC and are relevant to human MB.

Collaborating with a MB genomics group, we utilized whole genome sequencing (WGS) data and identified two chromosomal loci that are hotspots for rearrangement in Group 3 MB. Using histone chromatin immunoprecipitation sequencing (ChIP-seq) and expression profiling, we found that rearrangements at these loci activate the zinc-finger transcriptional repressors GFI1 and GFI1B by repositioning them adjacent to super-enhancers. Importantly, we demonstrated their functional relevance in an orthotopic transplantation model, where overexpression of either Gfi1 or Gfi1b cooperated strongly with Myc to drive MB formation in mice. These studies highlight a new mechanism for oncogene activation in MB and reveal GFI1/1B as highly prevalent drivers of Group 3 MB.

Although the oncogenic potentials of GFI1/1B have previously been studied in blood malignancies, their roles in MB are not well understood. We proceeded to identify the chromatin modifier Lysine demethylase 1 (Lsd1) as a key mediator of Gfi1 function in MB, and integration of ChIP-seq and gene expression data revealed a number of putative target genes and signaling pathways that may be co-regulated by Gfi1/1b and Lsd1. Given the critical interaction between Gfi1 and Lsd1 in these tumors, we tested several small molecule inhibitors of Lsd1 and found that they specifically reduced Gfi1-driven tumor cell growth both in vitro and in vivo. Together these studies confirm the importance of Lsd1 in Gfi1-driven MB and suggest that targeting Lsd1 pharmacologically may be a promising therapeutic strategy.