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      Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia

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          Abstract

          Background

          Characterization of novel fusion genes in acute leukemia is important for gaining information about leukemia genesis. We describe the characterization of a new ETV6 fusion gene in acute myeloid leukemia (AML) FAB M0 as a result of an uncommon translocation involving chromosomes 12 and 15.

          Methods

          The ETV6 locus at 12p13 was shown to be translocated and to constitute the 5' end of the fusion product by ETV6 break apart fluorescence in situ hybridisation (FISH). To identify a fusion partner 3' rapid amplification of cDNA-ends with polymerase chain reaction (RACE PCR) was performed followed by cloning and sequencing.

          Results

          The NTRK3 gene on chromosome 15 was found to constitute the 3' end of the fusion gene and the underlying ETV6-NTRK3 rearrangement was verified by reverse transcriptase PCR. No RNA of the reciprocal NTRK3- ETV6 fusion gene could be detected.

          Conclusion

          We have characterized a novel ETV6-NTRK3 fusion transcript which has not been previously described in AML FAB M0 by FISH and RACE PCR. ETV6-NTRK3 rearrangements have been described in secretory breast carcinoma and congenital fibrosarcoma.

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          A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.

          S Knezevich, Gino Lim, Huizhong W. Tao … (1998)
          Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of fibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate. CFS is histologically identical to adult-type fibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKC). Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.
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            ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.

            S Knezevich, M Garnett, Kristina Sørensen … (1998)
            Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.
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              ETV6: a versatile player in leukemogenesis.

              Stefan K Bohlander (2005)
              Alterations of the ets family transcription factor ETV6 (TEL) and the RUNT domain transcription factor RUNX1 (AML1) play pivotal roles in the leukemogenesis of various types of leukemia. While only three fusion partners of RUNX1 namely ETO, ETV6 and MTG16 have been described so far, there is a plethora of ETV6 fusion partners with about 20 partners described so far. Apart from forming fusion genes there are other genetic alterations of ETV6 including deletions, point mutations and possible alterations at the promoter level that might contribute to the malignant phenotype. This review will focus on ETV6 and on the different mechanisms that are used by this gene to cause leukemia.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diagn Pathol
                Title: Diagnostic Pathology
                Publisher: BioMed Central
                ISSN (Electronic): 1746-1596
                Publication date Collection: 2011
                Publication date (Electronic): 15 March 2011
                Volume: 6
                Page: 19
                Affiliations
                [1 ]Laboratory of Molecular Biology and Tumorcytogenetics, Department of Internal Medicine I, Krankenhaus der Barmherzigen Schwestern, Seilerstaette 4, 4010 Linz, Austria
                [2 ]Institute of Pathology, Krankenhaus der Barmherzigen Schwestern, Seilerstaette 4, 4010 Linz, Austria
                [3 ]Laboratory for Hematology, Department of Internal Medicine I, Krankenhaus der Barmherzigen Schwestern, Seilerstaette 4, 4010 Linz, Austria
                [4 ]Department of Internal Medicine I; Krankenhaus der Barmherzigen Schwestern, Seilerstaette 4, 4010 Linz, Austria
                [5 ]Institute of Laboratory Medicine BB&BS, Krankenhaus der Barmherzigen Schwestern, Seilerstaette 4, 4010 Linz, Austria
                Article
                Publisher ID: 1746-1596-6-19
                DOI: 10.1186/1746-1596-6-19
                PMC ID: 3063188
                PubMed ID: 21401966
                SO-VID: 3395252b-9dae-4692-b682-71ca306ced21
                Copyright © Copyright ©2011 Kralik et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 11 January 2011
                Date accepted : 15 March 2011
                Categories
                Subject: Research

                ScienceOpen disciplines: Pathology
                Data availability:
                ScienceOpen disciplines: Pathology

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