Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma

Abstract

The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.

FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1

“…In fact, these were the only recurrent imbalances, together with gain of 7q in 2 cases with ring chromosomes, in the cases investigated, emphasizing the pathogenetic importance of the fusion gene in LGFMS. Moreover, the deletions effectively remove most of the FUS and CREB3L2 portions that are not retained in the fusion gene, thereby explaining the absence of reciprocal fusion gene expression in most reported LGFMS cases (6,7).…”

“…Gene expression array (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], IHC analyses (cases 1, 2, 10, 11, and 20-24), ICC (cases 5 and 6), and/or SNP array (cases 1-9) were carried out on 24 LGFMS cases listed in Table 1. The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8).…”

“…The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8). One tumor (case 14) had the FUS-CREB3L1 fusion transcript.…”

“…Through these translocations, the chimeric genes FUS-CREB3L2 or FUS-CREB3L1, respectively, are created. At the molecular level, the 5 0 -part of FUS, encoding a transactivation domain, is fused to the 3 0 -part of CREB3L2 or CREB3L1, encoding a basic leucine zipper (bZIP) DNA-binding domain (5,7). A subset of LGFMS cases expresses the FUS-CREB3L2 fusion transcript but lacks the typical t(7;16) and instead harbors a supernumerary ring chromosome, which may contain the fusion gene, as the sole aberration (6,8).…”

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

“…EAF2 has also been shown to induce prostate cancer-cell apoptosis in xenograft tumours, and its expression is downregulated in prostate tumours (Xiao et al, 2003). CREB3L2 a cAMP-response element binding protein homologue that is fused to the FUS gene in fibromyxoid sarcomas (Storlazzi et al, 2003), was upregulated by R1881, but was not significantly upregulated by other AR ligands ( Figure 5). Serum/glucocorticoid-induced protein kinase-1, which stimulates AR activity and is important for prostate cancer-cell growth, is itself androgenregulated (Shanmugam et al, 2007), with rapid stimulation in its expression, which peaked at 24 h (25-fold) and decreased to near basal levels by 48 h. Interestingly, DHT did not stimulate serum/glucocorticoid-induced protein kinase expression at 24 h, whereas its expression was stimulated 2-, 5-, 1.8-and 3.9-fold by CPA, OHF, E2 and MPA, respectively.…”