Specificity of TLS-CHOP Rearrangement for Classic Myxoid/Round Cell Liposarcoma
2000; Elsevier BV; Volume: 2; Issue: 3 Linguagem: Inglês
10.1016/s1525-1578(10)60628-9
ISSN1943-7811
AutoresCristina R. Antonescu, Abul Elahi, Marcia Humphrey, Man Yee Lui, John H. Healey, Murray F. Brennan, James M. Woodruff, Suresh C. Jhanwar, Marc Ladanyi,
Tópico(s)Cancer-related molecular mechanisms research
ResumoMyxoid liposarcoma (LS), the most common subtype of LS, is known to be characterized by the specific t(12;16) resulting in a TLS-CHOP fusion in almost all cases. We wished to address the following questions: (i) Is this genetic hallmark also present in other types of LS with predominant myxoid change? (ii) What is the proportion of cases with the variant EWS-CHOP fusion? (iii) What is the optimal approach for Southern blot detection of TLS breakpoints? We identified 59 LS characterized histologically by >90% myxoid component, in which frozen tissue tumor was available for DNA extraction. These 59 LS with myxoid features were divided into 2 groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS (WDLS) with a predominant (>90%) myxoid component. Within the myxoid LS group, 29 tumors were low grade and 13 high grade (>20% round cell component). Among the 17 predominantly myxoid WDLS, there were 15 low grade and 2 focally high grade tumors. In addition, we selected as control group, 20 LS of other histological types with minimal or no myxoid change (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas. Southern blot analysis was performed in all cases using a CHOP cDNA probe, and in all CHOP rearranged cases using a TLS cDNA probe. Probe/enzyme combinations for Southern blot analysis were CHOP exon 3–4 cDNA probe with BamHI or SacI, TLS exon 3–6 cDNA probe with BclI. All 42 cases of myxoid LS showed a CHOP rearrangement and 38 of them also had a TLS rearrangement. Among the 4 myxoid LS without Southern blot evidence of TLS rearrangement, 1 showed an EWS-CHOP fusion by Southern blotting and reverse transcriptase-polymerase chain reaction and in another case, reverse transcriptase-polymerase chain reaction detected a TLS-CHOP fusion transcript. None of the predominantly myxoid WDLS and none of the tumors included in the control group showed rearranegements with CHOP probe. In addition, 12 predominantly myxoid WDLS, 10 other LS, and 5 myxofibrosarcoma from the control group were also tested for TLS rearrangement; all were negative. The TLS-CHOP fusion is highly sensitive and specific for the entity of classic myxoid/round cell LS. Other types of LS, even with a predominant myxoid component, lack the TLS-CHOP rearrangement, confirming that they represent a genetically distinct group of LS. The prevalence of the EWS-CHOP variant fusion was approximately 2% in this series. The optimal enzyme for TLS genomic breakpoint detection is BclI. Myxoid liposarcoma (LS), the most common subtype of LS, is known to be characterized by the specific t(12;16) resulting in a TLS-CHOP fusion in almost all cases. We wished to address the following questions: (i) Is this genetic hallmark also present in other types of LS with predominant myxoid change? (ii) What is the proportion of cases with the variant EWS-CHOP fusion? (iii) What is the optimal approach for Southern blot detection of TLS breakpoints? We identified 59 LS characterized histologically by >90% myxoid component, in which frozen tissue tumor was available for DNA extraction. These 59 LS with myxoid features were divided into 2 groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS (WDLS) with a predominant (>90%) myxoid component. Within the myxoid LS group, 29 tumors were low grade and 13 high grade (>20% round cell component). Among the 17 predominantly myxoid WDLS, there were 15 low grade and 2 focally high grade tumors. In addition, we selected as control group, 20 LS of other histological types with minimal or no myxoid change (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas. Southern blot analysis was performed in all cases using a CHOP cDNA probe, and in all CHOP rearranged cases using a TLS cDNA probe. Probe/enzyme combinations for Southern blot analysis were CHOP exon 3–4 cDNA probe with BamHI or SacI, TLS exon 3–6 cDNA probe with BclI. All 42 cases of myxoid LS showed a CHOP rearrangement and 38 of them also had a TLS rearrangement. Among the 4 myxoid LS without Southern blot evidence of TLS rearrangement, 1 showed an EWS-CHOP fusion by Southern blotting and reverse transcriptase-polymerase chain reaction and in another case, reverse transcriptase-polymerase chain reaction detected a TLS-CHOP fusion transcript. None of the predominantly myxoid WDLS and none of the tumors included in the control group showed rearranegements with CHOP probe. In addition, 12 predominantly myxoid WDLS, 10 other LS, and 5 myxofibrosarcoma from the control group were also tested for TLS rearrangement; all were negative. The TLS-CHOP fusion is highly sensitive and specific for the entity of classic myxoid/round cell LS. Other types of LS, even with a predominant myxoid component, lack the TLS-CHOP rearrangement, confirming that they represent a genetically distinct group of LS. The prevalence of the EWS-CHOP variant fusion was approximately 2% in this series. The optimal enzyme for TLS genomic breakpoint detection is BclI. Myxoid liposarcoma (LS) is the most common subtype of LS and occurs predominantly in the extremities1Enzinger FM Weiss SW Liposarcoma (chapter 17).in: Enzinger FM Weiss SW Soft Tissue Tumors. 3rd ed. Mosby, St. Louis, MO1995: 431-466Google Scholar, 2Kilpatrick SE Doyon J Choong PF Sim FH Nascimento AG The clinicopathologic spectrum of myxoid and round cell liposarcoma: a study of 95 cases.Cancer. 1996; 77: 1450-1458Crossref PubMed Scopus (242) Google Scholar A subset of cases show histological progression to round cell histology, which is associated with a significantly poorer prognosis.2Kilpatrick SE Doyon J Choong PF Sim FH Nascimento AG The clinicopathologic spectrum of myxoid and round cell liposarcoma: a study of 95 cases.Cancer. 1996; 77: 1450-1458Crossref PubMed Scopus (242) Google Scholar The karyotypic hallmark of myxoid LS is the t(12;16)(q13;p11), present cytogenetically in >90% of the cases.3Heim S Mitelman F Cancer Cytogenetics. 2nd ed. Wiley-Liss, New York1995: 484-489Google Scholar The translocation leads to the fusion of the CHOP and TLS genes at 12q13 and 16p11, respectively, and the generation of a TLS-CHOP hybrid protein.4Aman P Ron D Mandahl N Fioretos T Heim S Arheden K Willen H Rydholm A Mitelman F Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).Genes Chromosomes Cancer. 1992; 5: 278-285Crossref PubMed Scopus (261) Google Scholar, 5Crozat A Aman P Mandahl N Ron D Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.Nature. 1993; 363: 640-644Crossref PubMed Scopus (757) Google Scholar, 6Rabbitts TH Forster A Larson R Nathan P Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.Nat Genet. 1993; 4: 175-180Crossref PubMed Scopus (481) Google Scholar In 4 cases of myxoid LS, a variant chromosomal translocation has been described, t(12;22), in which CHOP fuses instead with EWS, a gene highly related to TLS.7Panagopoulos I Hoglund M Mertens F Mandahl N Mitelman F Aman P Fusion of the EWS and CHOP genes in myxoid liposarcoma.Oncogene. 1996; 12: 489-494PubMed Google Scholar, 8Dal Cin P Sciot R Panagopoulos I Aman P Samson I Mandahl N Mitelman F Van Den Berghe H Fletcher CD Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features.J Pathol. 1997; 182: 437-441Crossref PubMed Scopus (100) Google Scholar Different cytogenetic features and their underlying molecular alterations define distinct entities among LS. A strong and specific association of the t(12;16) with myxoid LS has been confirmed by most cytogenetic and molecular analyses.4Aman P Ron D Mandahl N Fioretos T Heim S Arheden K Willen H Rydholm A Mitelman F Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11).Genes Chromosomes Cancer. 1992; 5: 278-285Crossref PubMed Scopus (261) Google Scholar, 9Knight JC Renwick PJ Dal Cin P Van Den Berghe H Fletcher CDM Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.Cancer Res. 1995; 55: 24-27PubMed Google Scholar, 10Sreekantaiah C Karakousis CP Leong SP Sandberg AA Cytogenetic findings in liposarcoma correlate with histopathologic subtypes.Cancer. 1992; 69: 2484-2495Crossref PubMed Scopus (122) Google Scholar, 11Tallini G Akerman M Dal Cin P de Wever I Fletcher CD Mandahl N Mertens F Mitelman F Rosai J Rydholm A Sciot R Van Den Berghe H Van den Ven W Vanni R Willen H Combined morphologic and karyotypic study of 28 myxoid liposarcomas: implications for a revised morphologic typing (a report from the CHAMP Group).Am J Surg Pathol. 1996; 20: 1047-1055Crossref PubMed Scopus (97) Google Scholar, 12Kuroda M Ishida T Horiuchi H Kida N Uozaki H Takeuchi H Tsuji K Imamura T Mori S Machinami R Watanabe T Chimeric TLS/FUS-CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma.Am J Pathol. 1995; 147: 1221-1227PubMed Google Scholar, 13Hisaoka M Tseiji S Morimitsu Y Hashimoto H Shimajiri S Komiya S Ushijima M Detection of TLS/FUS-CHOP fusion transcripts in myxoid and round cell liposarcomas by nested reverse transcription-polymerase chain reaction using archival paraffin-embedded tissues.Diagn Mol Pathol. 1998; 7: 96-101Crossref PubMed Scopus (77) Google Scholar The same translocation is present in pure round cell LS and combined myxoid and round cell LS, confirming the biological continuum between these two forms of LS, proposed on histopathological grounds.9Knight JC Renwick PJ Dal Cin P Van Den Berghe H Fletcher CDM Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.Cancer Res. 1995; 55: 24-27PubMed Google Scholar, 11Tallini G Akerman M Dal Cin P de Wever I Fletcher CD Mandahl N Mertens F Mitelman F Rosai J Rydholm A Sciot R Van Den Berghe H Van den Ven W Vanni R Willen H Combined morphologic and karyotypic study of 28 myxoid liposarcomas: implications for a revised morphologic typing (a report from the CHAMP Group).Am J Surg Pathol. 1996; 20: 1047-1055Crossref PubMed Scopus (97) Google Scholar, 12Kuroda M Ishida T Horiuchi H Kida N Uozaki H Takeuchi H Tsuji K Imamura T Mori S Machinami R Watanabe T Chimeric TLS/FUS-CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma.Am J Pathol. 1995; 147: 1221-1227PubMed Google Scholar, 13Hisaoka M Tseiji S Morimitsu Y Hashimoto H Shimajiri S Komiya S Ushijima M Detection of TLS/FUS-CHOP fusion transcripts in myxoid and round cell liposarcomas by nested reverse transcription-polymerase chain reaction using archival paraffin-embedded tissues.Diagn Mol Pathol. 1998; 7: 96-101Crossref PubMed Scopus (77) Google Scholar In contrast, well-differentiated LS (WDLS) and pleomorphic LS contain no specific recurrent translocation. Instead, WDLS are characterized by cytogenetic evidence of gene amplification (giant marker chromosomes, ring chromosomes, double minutes), whereas pleomorphic LS typically show highly complex karyotypes.10Sreekantaiah C Karakousis CP Leong SP Sandberg AA Cytogenetic findings in liposarcoma correlate with histopathologic subtypes.Cancer. 1992; 69: 2484-2495Crossref PubMed Scopus (122) Google Scholar, 14Fletcher CD Akerman M Dal Cin P de Wever I Mandahl N Mertens F Mitelman Rosai J Rydholm A Sciot R Tallini G Van Den Berghe H Van de Ven W Vanni R Willen H Correlation between clinicopathological features and karyotype in lipomatous tumors: a report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study Group.Am J Pathol. 1996; 148: 623-630PubMed Google Scholar, 15Rosai J Akerman M Dal Cin P de Wever I Fletcher CD Mandahl N Mertens F Mitelman F Rydholm A Sciot R Tallini G Van Den Berghe H Van de Ven W Vanni R Willen H Combined morphologic and karyotypic study of 59 atypical lipomatous tumors: evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group).Am J Surg Pathol. 1996; 20: 1182-1189Crossref PubMed Scopus (186) Google Scholar Nonetheless, a single recent report has suggested that TLS-CHOP fusion transcripts may also be present in pleomorphic LS and WDLS.16Willeke F Ridder R Mechtersheimer G Schwarzbach M Duwe A Weitz J Lehnert T Herfarth C von Knebel D Analysis of FUS-CHOP fusion transcripts in different types of soft tissue liposarcoma and their diagnostic implications.Clin Cancer Res. 1998; 4: 1779-1784PubMed Google Scholar The existence of a mixed tumor with combined features of myxoid LS and WDLS has been proposed based on cases of LS showing histological features of both.11Tallini G Akerman M Dal Cin P de Wever I Fletcher CD Mandahl N Mertens F Mitelman F Rosai J Rydholm A Sciot R Van Den Berghe H Van den Ven W Vanni R Willen H Combined morphologic and karyotypic study of 28 myxoid liposarcomas: implications for a revised morphologic typing (a report from the CHAMP Group).Am J Surg Pathol. 1996; 20: 1047-1055Crossref PubMed Scopus (97) Google Scholar For instance, up to one-third of WDLS show some degree of myxoid change.15Rosai J Akerman M Dal Cin P de Wever I Fletcher CD Mandahl N Mertens F Mitelman F Rydholm A Sciot R Tallini G Van Den Berghe H Van de Ven W Vanni R Willen H Combined morphologic and karyotypic study of 59 atypical lipomatous tumors: evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group).Am J Surg Pathol. 1996; 20: 1182-1189Crossref PubMed Scopus (186) Google Scholar Furthermore, rare cases of myxoid LS have shown apparent dedifferentiation, a phenomenon typically associated with WDLS.17Mentzel T Fletcher CD Dedifferentiated myxoid liposarcoma: a clinicopathological study suggesting a closer relationship between myxoid and well-differentiated liposarcoma.Histopathology. 1997; 30: 457-463Crossref PubMed Scopus (60) Google Scholar These problematic tumors showing combined features of myxoid LS and WDLS, most often seen in the retroperitoneum, have not been systematically studied for the presence of the t(12;16). Thus the issue of the histological specificity of the TLS-CHOP fusion and the broader question of the biological relationship among different forms of LS have not been completely resolved. Aside from these biological and nosological questions, the differential diagnosis of myxoid LS can be sometimes quite difficult, due to overlapping morphological features with other myxoid neoplasms, myxofibrosarcoma in particular. In the present study, we sought to address these issues by systematically studying myxoid LS, WDLS, pleomorphic LS, WDLS with extensive myxoid change, and myxofibrosarcomas for the TLS-CHOP rearrangement by Southern blotting. The TLS genomic breaks are clustered in introns 5 and 7,18Panagopoulos I Mandahl N Mitelman F Aman P Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).Oncogene. 1995; 11: 1133-1137PubMed Google Scholar, 19Kanoe H Nakayama T Hosaka T Murakami H Yamamoto H Nakashima Y Tsuboyama TNT Ron D Sasaki MS Toguchida J Characteristics of genomic breakpoints in TLS-CHOP translocations in liposcarcomas suggest the involvement of Translin and topoisomerase II in the process of translocation.Oncogene. 1999; 18: 721-729Crossref PubMed Scopus (57) Google Scholar whereas the vast majority of CHOP breakpoints occur in intron 1 or immediately upstream of exon 1;19Kanoe H Nakayama T Hosaka T Murakami H Yamamoto H Nakashima Y Tsuboyama TNT Ron D Sasaki MS Toguchida J Characteristics of genomic breakpoints in TLS-CHOP translocations in liposcarcomas suggest the involvement of Translin and topoisomerase II in the process of translocation.Oncogene. 1999; 18: 721-729Crossref PubMed Scopus (57) Google Scholar in both genes, the breakpoint regions are relatively small ( 90% myxoid areas (including areas of round cell change), operated at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1987 and 1998, in which frozen tumor was available for DNA extraction. Patient materials were procured under MSKCC protocol 90–049 approved by our Institutional Review Board. The 59 LS with myxoid features were divided into two groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS with a predominant (>90%) myxoid change (predominantly myxoid WDLS). Within the myxoid LS group, 28 tumors arose in the extremities, 4 in the pelvic girdle, and 3 in the retroperitoneum, and 7 were multifocal. Histologically, 29 of the myxoid LS were low grade (Figure 1A) and 13 were high grade (defined as >20% round cell component). The predominantly myxoid WDLS tumors were located in the following axial sites: retroperitoneum (13 cases), pelvis (2 cases), intraabdominal (1 case), and mediastinum (1 case). No cases of this histological type presented in the extremities. The majority of predominantly myxoid WDLS were histologically low grade (15 cases), showing focal areas (by the study criteria <10%) of lipoma-like or sclerosing LS, diagnostic of WDLS (Figure 1B). In the remaining 2 cases of predominantly myxoid WDLS areas of dedifferentiation into a high grade spindle cell sarcoma were intermixed with the myxoid component. In addition, we selected a control group of 20 LS of other histological types (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas for which adequate frozen tumor was available for molecular analysis. The 17 cases of WDLS included in the control group showed lesser or absent myxoid change, as follows: 6 cases with 25 to 50% myxoid change, 5 cases with 90% myxoid histology, 42 cases were classified as classic myxoid LS. All of these 42 myxoid LS showed a CHOP rearrangement, and in 38 of them (90%) TLS rearrangement was also demonstrated (Table 1). Regarding the CHOP analysis, in 35 cases (83%) the CHOP rearrangement was detected with both BamHI and SacI (Figure 3), in 3 cases only with BamHI (germline pattern with SacI), and in 3 cases only with SacI (germline pattern in with BamHI in 1 case and inadequate DNA for BamHI digest in 2 cases). Finally, one case that was germline with BamHI and had inadequate DNA for SacI had shown rearrangements previously with two other restriction enzymes (EcoRI and HindIII). Regarding the detection of TLS rearrangements, 32 of 37 cases (86%) studied with BclI digests were positive (Figure 4). In 6 additional cases, TLS rearrangement was detected with other restriction enzymes, including EcoRI,BamHI, and PstI (see Table 1). Among the 4/42 cases that were not rearranged with TLS probe, 1 case could not be further tested due to degraded DNA, while 3 had sufficient DNA for further Southern blot analysis which showed a germline pattern with 4 additional restriction enzymes (BamHI,SacI, EcoRI, HindIII). Unfortunately, karyotypic data were not available in any of these 4TLS-germline cases. One of the latter was tested for TLS-CHOP by reverse transcriptase-polymerase chain reaction (RT-PCR) and found to have the relatively uncommon fusion of TLS exon 8 to CHOP exon 2 (results not shown). The remaining 2 cases of myxoid LS germline for TLS in 5 different restriction digests were tested for EWSrearrangement. One case showed a rearranged EWS band in HindIII-digested tumor DNA. RT-PCR analysis confirmed the presence of the EWS-CHOP fusion in this case, which is presented in more detail elsewhere.22Antonescu CR Elahi A Healey JH Brennan MF Lui MY Lewis JJ Jhanwar SC Woodruff JM Ladanyi M Monoclonality of multifocal myxoid liposarcoma: confirmation by analysis of TLS-CHOP or EWS-CHOP rearrangements.Clin Cancer Res. 2000; (in press)PubMed Google Scholar This left one TLS-germline CHOP-rearranged case in which the putative CHOP translocation could not be further defined at the molecular level.Table 1Summary of Results CHOPTLSResults by restriction digestResults by restriction digestHistologic groupOverall resultBamHI and SacI digests*Except for this column, which shows the number of cases with identical results for both enzymes, in cells where the number of cases is less than n, the remaining cases were not studied with the enzyme in question, unless otherwise specified.BamHISacIHindIIIEcoRIOverall resultBclIBamHIPstIMyxoid LS (n = 42)42 R35 R38 R38 R1 R1 R38/42 R†Includes 2 cases that showed TLS rearrangement in EcoRI digests only; for details on 4 cases without detectable TLS rearrangement, see Results.32 R3 R1 R2 G3 G5 G2 F1 F2 FPredominantly myxoid WDLS (n = 17)17 G17 G17 G17 G6 G3 G12 G10 G2 G2 GWDLS with minor or no myxoid areas (n = 17)17 G14 G17 G14 G8 G4 G9 G2 G6 G2 G1 FPleomorphic LS (n = 3)3 G3 G3 G3 G2 GND1 G1 GNDNDMyxofibrosarcoma (n = 13)13 G12 G13 G12 G7 G4 G5 G4 GND1 GLS, liposarcoma; WDLS, well-differentiated LS; R, rearranged; G, germline; F, failure; ND, not done.* Except for this column, which shows the number of cases with identical results for both enzymes, in cells where the number of cases is less than n, the remaining cases were not studied with the enzyme in question, unless otherwise specified.† Includes 2 cases that showed TLS rearrangement in EcoRI digests only; for details on 4 cases without detectable TLS rearrangement, see Results. Open table in a new tab Figure 4TLS rearrangement analysis by Southern blotting. Rearranged bands are seen in BclI-digested genomic DNA in two cases of classic myxoid LS (LS2 and LS15), but not in a case of predominantly myxoid WDLS (LS56) using a TLS exon 3–6 cDNA probe (see Methods and Figure 2).View Large Image Figure ViewerDownload Hi-res image Download (PPT) LS, liposarcoma; WDLS, well-differentiated LS; R, rearranged; G, germline; F, failure; ND, not done. Among the WDLS with >90% myxoid histology, all of the cases tested had a germline pattern with CHOP probe by both BamHI and SacI digests. In addition, 12 of 17 cases were also tested for TLS rearrangements and showed a germline profile: 8 by BclI digest only, 2 by both BclI and PstI, and 2 by BamHI digest only. The other lipomatous tumors composing the control group, including LS with variable myxoid component (25 to 50%) or with absent or focal myxoid change had a germline pattern with CHOP probe: 14/17 cases with both BamHI and SacI and 3/17 cases only with BamHI (technical failure with SacI digest). In 9 cases, TLS was also studied and was not rearranged in any case. All 3 pleomorphic LS had a germline pattern for CHOP using both BamHI and SacI, and in 2/3 also with HindIII. Southern blot analysis with the TLS cDNA probe was performed in 1 of the 3 pleomorphic LS and showed a germline pattern in BclI-digested DNA. All myxofibrosarcomas had a germline profile with CHOP(12/13 cases with both BamHI and SacI, and 1/13 with BamHI, EcoRI, and HindIII). Five cases were also tested for TLS and showed no genomic rearrangement. The CHOP gene encodes a member of leucine zipper transcription factor family implicated in adipocyte differentiation and growth arrest.23Ron D Habener JF CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant negative inhibitor of gene transcription.Genes Dev. 1992; 6: 439-453Crossref PubMed Scopus (985) Google Scholar, 24Butterwith SC Molecular events in adipocyte development.Pharmacol Ther. 1994; 61: 399-411Crossref PubMed Scopus (62) Google Scholar In myxoid LS, most of the CHOP gene is fused to the 5′ portion of TLS (for translocated in liposarcoma),6Rabbitts TH Forster A Larson R Nathan P Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.Nat Genet. 1993; 4: 175-180Crossref PubMed Scopus (481) Google Scholar also known as FUS (for fusion).5Crozat A Aman P Mandahl N Ron D Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.Nature. 1993; 363: 640-644Crossref PubMed Scopus (757) Google Scholar The fusion gene encodes a protein that consists of the amino terminus of TLS fused to the full-length CHOP-coding region. The oncogenic effect of TLS-CHOP may be mediated at least in part by inhibition of pre-adipocyte differentiation.25Kuroda M Ishida T Takanashi M Satoh M Machinami R Watanabe T Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein.Am J Pathol. 1997; 151: 735-744PubMed Google Scholar, 26Adelmant G Gilbert JD Freytag SO Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLS-CHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function.J Biol Chem. 1998; 273: 15574-15581Crossref PubMed Scopus (68) Google Scholar, 27Ron D TLS-CHOP and the role of RNA-binding proteins in oncogenic transformation.Curr Top Microbiol Immunol. 1997; 220: 131-142PubMed Google Scholar The TLS genomic breaks are clustered in introns 5 and 718Panagopoulos I Mandahl N Mitelman F Aman P Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21).Oncogene. 1995; 11: 1133-1137PubMed Google Scholar (Figure 2),19Kanoe H Nakayama T Hosaka T Murakami H Yamamoto H Nakashima Y Tsuboyama TNT Ron D Sasaki MS Toguchida J Characteristics of genomic breakpoints in TLS-CHOP translocations in
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