Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes

Abstract

Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangementst(16;17)(q22;p13) -was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/ mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.

Percutaneous Doxycycline Treatment of Aneurysmal Bone Cysts With Low Recurrence Rate: A Preliminary Report

“…Discussion ABC is considered a mesenchymal neoplasm [10,[30][31][32] characterized by spindle cell proliferation with TRE17/ USP6 as the major oncogene [10,[30][31][32]. The translocational event on chromosomal bands 16q22 and 17p13, with TRE17/USP6 oncogene rearrangement, is found in 69% of primary ABCs [10,[30][31][32].…”

“…The translocational event on chromosomal bands 16q22 and 17p13, with TRE17/USP6 oncogene rearrangement, is found in 69% of primary ABCs [10,[30][31][32]. The pathogenesis of the ABC is now believed to be a novel oncogenic mechanism with TRE17/USP6 transcription associated with upregulation of VEGF and MMP production, increased osteoclastic activity, and TRE17/USP6 promotion that blocks osteoblastic maturation through an autocrine mechanism involving bone morphogenic protein dysregulation [5,24,43].…”

“…ABCs demonstrate specific translocational events, most commonly found on chromosomal bands 16q22 and 17p13 with TRE17/ubiquitin carboxyl-terminal hydrolase 6 (USP6) oncogene rearrangements found in primary ABCs [2,3,10,[30][31][32]38]. Multinucleated giant cells in ABCs express osteolytic features of osteoclasts with high levels of matrix metalloproteinases (MMP-9 and MMP-10), tartarate-resistant acid phosphatase, and cathepsin K [23,26].…”

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

“…[24][25][26][27] Most notably, Usp18 (previously Ubp43) levels have been shown to be specifically upregulated in mice expressing the RUNX1/CBFA2T1 chimera, 25 and USP33 is overexpressed in B-ALL as compared with T-ALL, 26 suggesting that deregulation of USPs may be important in leukemogenesis. Furthermore, a recurrent rearrangement involving USP6 has previously been described in aneurysmal bone cysts (ABC); the t(16;17)(q22;p13) which places the whole coding sequence of USP6 under the transcriptional control of the highly active CDH11 promotor.…”

USP6 genetic rearrangements in cellular fibroma of tendon sheath

“…8 USP6 rearrangements also occur in a majority of aneurysmal bone cysts; however, the fusion partners differ from those seen in nodular fasciitis. [9][10][11][12][13][14] As a subset of cellular fibromas of tendon sheath has overlapping histological features with nodular fasciitis, we hypothesized that cellular fibroma of tendon sheath may be a tenosynovial variant of nodular fasciitis and harbor USP6 genetic rearrangements. We tested a series of classic and cellular fibromas of tendon sheath for USP6 and MYH9 rearrangements and MYH9-USP6 and CDH11-USP6 fusion products.…”