A novel zinc finger gene is fused to EWS in small round cell tumor

Abstract

Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to ®ve dierent members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Dierent classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc ®nger Sarcoma Gene), is a putative Cys 2 -His 2 zinc ®nger protein which contains a POZ transcriptional repressor-like domain at the Nterminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc ®nger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the ®rst example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma. Oncogene (2000) 19, 3799 ± 3804.Keywords: sarcoma; EWS; fusion; POZ/BTB domain; zinc ®ngerWe present here the ®rst report of an intrachromosomal rearrangement of chromosome 22 activating EWS by fusion with a novel zinc ®nger gene in a soft tissue sarcoma.The tumor occurred in a male boy aged 16 years, presenting with a pulmonary metastasis 2 years after a primary tumor of the chest wall. Histologically both primary and metastatic tumors were highly suggesting for pPNET, possibly Askin-Rosai type owing to the primary site. Immunophenotyping performed on primary and metastatic tumor showed reactivity for synaptophysin (AO10, Dako) and NSE (MIG-N3, Sambio) and the same small clusters and scattered cells decorated with desmin (D33, Dako) and lowweight cytocheratins (CAM 5.2, Becton Dickinson). A negative staining was observed with neuro®laments (RPN1105, Amersham) and MIC2 antigen (013, Signet). The latter ®nding, being MIC2 a hallmark of pPNET, prompted the diagnosis of a small round cell tumor with multidirectional dierentiation rather than of pPNET.Cytogenetic and¯uorescence in situ hybridization (FISH) analyses of the small round cell sarcoma under study revealed a translocation t(1;22)(p36.1;q12) (Figure 1a ± c). No structural involvement of chromosome 11, indicative of the translocation t(11;22) described in 90% of Ewing's tumors (Turc-Carel et al., 1983), (Sorensen et al., 1994) was observed.To rule out a molecular fusion of EWS with already known partners, we performed RT ± PCR on tumor RNA to assess the presence of EWS/FLI-1 (May et al., and Gerald, 1994;Gerald et al., 1995) fusion products. We could not detect PCR products with any primer set (data not shown).We tested the tumor DNA for the presence of EWS gene alterations by Southern blot analyses using as probe a partial EWS cDNA clone (Delattre et al., 1992). An abnormal r...

POZ-, AT-hook-, and Zinc Finger-containing Protein (PATZ) Interacts with Human Oncogene B Cell Lymphoma 6 (BCL6) and Is Required for Its Negative Autoregulation

“…In the present study, starting from a yeast two-hybrid screening using PATZ1 full-length cDNA as bait, we demonstrate that PATZ associates with BCL6, 3 a protein that shares with PATZ the N-terminal POZ domain, responsible for such association, and is involved in B and T cell development and lymphomagenesis (13)(14)(15)38). We show that PATZ participates in BCL6 function by enhancing its activity of transcriptional repressor on BCL6 promoter in GC-derived lymphoma B cells.…”

“…Indeed, PATZ1 is rearranged and deleted in small round cell sarcoma (3), and the chromosomal region where it is located (22q12) is in the human fragile site FRA22B, which suffers loss of heterozygosity in tumors (7). Increased expression of PATZ1 mRNA has been observed in human malignant neoplasias, including colorectal (8), breast (9), and testicular (10) tumors.…”

“…The PATZ1 gene encodes four main alternative proteins ranging from 537 to 687 amino acids that contain an N-terminal POZ domain, one or two AT-hooks in the central region, and four to six C2H2 zinc finger motifs at the C terminus (1)(2)(3). Both the AT-hooks and the POZ domain are characteristic of protein factors involved in gene transcription by interacting with a number of other protein factors.…”

Profile of Ets gene expression in human breast carcinoma

“…Chromosomal translo-Ets Expression in Breast Cancer cations involving several Ets genes are associated with Ewing's sarcomas (e.g., EWS-Fli1 and EWS-Erg) 4,5 and leukemia (e.g., Tel/Etv6-PDGFRb in chronic myelomonocytic leukemia and Tel/ Etv6-AML1 in childhood B cell-lineage acute lymphoblastic leukemia). 6,7 These chromosomal alterations result in either the inappropriate expression level or their expression as fusions with other proteins, both of which are believed to contribute to oncogenic transformation by deregulating downstream gene transcription.…”

POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) inhibits endothelial cell senescence through a p53 dependent pathway

“…13 In carcinogenesis, PATZ1 has been found to fuse to the Ewing sarcoma gene (EWS) by a submicroscopic inversion of 22q, resulting in activation of EWS in soft tissue sarcoma, suggesting that PATZ1 might have a potential tumor suppressor function. 16 PATZ1 could also be a potential proto-oncogene in colorectal cancer, as PATZ1 expression is increased in colorectal cancer tissues, PATZ1 upregulation promotes cell growth and its knockdown inhibits cell proliferation. 12 Recently, PATZ1 was reported to have a crucial role in normal male gametogenesis, and its upregulation and mislocalization from the nucleus to the cytosol was associated with the development of testicular tumors.…”