Aneurysmal bone cyst (ABC) is a locally recurrent bone lesion that has been regarded as a reactive process. Recently, a neoplastic basis in primary ABC was evidenced by demonstration of clonal chromosome band 17p13 translocations that place the USP6 (TRE2 or TRE17) oncogene under the regulatory influence of the highly active CDH11 promoter. Herein, we report CDH11 and/or USP6 rearrangements in 36 of 52 primary ABCs (69%), of which 10 had CDH11-USP6 fusion, 23 had variant USP6 rearrangements without CDH11 rearrangement, and three had variant CDH11 rearrangements without USP6 rearrangement. USP6 and CDH11 rearrangements were restricted to spindle cells in the ABC and were not found in multinucleated giant cells, inflammatory cells, endothelial cells, or osteoblasts. CDH11 and USP6 rearrangements did not correlate with recurrence-free survival, or with other clinicopathological features. CDH11 and USP6 rearrangements were not found in any of 17 secondary ABC associated with giant cell tumor, chondroblastoma, osteoblastoma, and fibrous dysplasia. These findings demonstrate that primary ABC are mesenchymal neoplasms exhibiting USP6 and/or CDH11 oncogenic rearrangements. By contrast, secondary ABC lack CDH11 and USP6 rearrangements, and although morphological mimics of primary ABC, appear to represent a non-specific morphological pattern of a diverse group of non-ABC neoplasms.

MITF, TFE3, TFEB, and TFEC comprise a transcription factor family (MiT) that regulates key developmental pathways in several cell lineages. Like MYC, MiT members are basic helix-loop-helix-leucine zipper transcription factors. MiT members share virtually perfect homology in their DNA binding domains and bind a common DNA motif. Translocations of TFE3 occur in specific subsets of human renal cell carcinomas and in alveolar soft part sarcomas. Although multiple translocation partners are fused to TFE3, each translocation product retains TFE3's basic helix-loop-helix leucine zipper. We have identified the genes fused by the chromosomal translocation t(6;11)(p21.1;q13), characteristic of another subset of renal neoplasms. In two primary tumors we found that Alpha, an intronless gene, rearranges with the first intron of TFEB, just upstream of TFEB's initiation ATG, preserving the entire TFEB coding sequence. Fluorescence in situ hybridization confirmed the involvement of both TFEB and Alpha in this translocation. Although the Alpha promoter drives expression of this fusion gene, the Alpha gene does not contribute to the ORF. Whereas TFE3 is typically fused to partner proteins in subsets of renal tumors, we found that wild-type, unfused TFE3 stimulates clonogenic growth in a cell-based assay, suggesting that dysregulated expression, rather than altered function of TFEB or TFE3 fusions, may confer neoplastic properties, a mechanism reminiscent of MYC activation by promoter substitution in Burkitt's lymphoma. Alpha-TFEB is thus identified as a fusion gene in a subset of pediatric renal neoplasms.M ITF, TFE3, TFEB, and TFEC are closely related basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors (1-8) that may homo-or heterodimerize in all combinations to bind DNA (9). These factors share sequence homology in their DNA-contacting basic domains (10), as well as activation domains, and recognize identical DNA sequences (9), suggesting that they may regulate similar downstream targets. Genetic and biochemical studies have revealed functional overlap of MiT activity in certain developmental lineages. Specifically, use of knockout mice by Jenkins and colleagues (8) has elegantly demonstrated that, whereas mutation of either Mitf or TFE3 in mice does not disrupt osteoclast development, mutation of both genes or presence of a dominant-negative allele produces severe osteopetrosis. Homozygous mutation of MITF in the mouse is particularly devastating to the melanocyte lineage, resulting in failure of melanocyte development (5). In humans, Mitf haploinsufficiency results in type IIa Waardenburg syndrome (11). Mice homozygous null for TFE3 or TFEC had no recognized abnormalities (8), but TFEB nulls exhibited embryonic lethality associated with placental vascular defects (12). In addition, Mitf and TFE3 have been found to undergo identical modifications after cytokine stimulation (13), and MITF has been shown to directly regulate BCL2, a key apoptotic regulator, in a manner important for melanocyte and melanoma surv...