Role of the LIM domain binding protein LDB1 and the LIM only factor LMO4 in SHH subgroup medulloblastoma

Recent genomic analyses of medulloblastoma, a malignant tumor comprising ˜15% of pediatric brain cancers, have identified distinct somatic alterations occurring in specific molecular subgroups of the disease. These findings have shed light on new pathways which may be involved in these subgroups. For example, large-scale sequencing and copy number studies have identified inactivating mutations of LIM domain binding 1 (LDB1) and amplifications of the LDB1 interacting protein, LIM-only 4 (LMO4) in 7% and 1.1% of SHH-subgroup medulloblastoma (SHH-MB), respectively. Cerebellar granule neuron precursors (CGNPs) are thought to be the cell-of-origin of the SHH-MB and therefore represent the ideal cell type to study these novel candidate genes in vitro and in vivo. Lmo4 expression was found to stimulate CGNP proliferation. CGNPs manipulated for Lmo4 or Ldb1 ex vivo are now being transplanted into mice, and any tumors arising will be further characterized in terms of downstream pathway activity.