Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.

Autor: Bossi D; Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy., Carlomagno F; Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy., Pallavicini I; Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy., Pruneri G; Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy., Trubia M; Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy., Raviele PR; Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy., Marinelli A; Department of Biosciences, University of Milan, Milan, Italy., Anaganti S; Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy., Cox MC; Department of Hematology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy., Viale G; Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy., Santoro M; Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy. Electronic address: masantor@unina.it., Di Fiore PP; Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy; Department of Scienze della Salute, University of Milan, Via di Rudinì 8, 20122 Milan, Italy; IFOM, FIRC Institute of Molecular Oncology, Milan, Italy. Electronic address: pierpaolo.difiore@ifom.eu., Minucci S; Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy. Electronic address: saverio.minucci@ieo.eu.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2014 Mar; Vol. 8 (2), pp. 221-31. Date of Electronic Publication: 2013 Nov 19.
DOI: 10.1016/j.molonc.2013.11.004
Abstrakt: The RET (REarranged during Transfection) receptor tyrosine kinase is targeted by oncogenic rearrangements in thyroid and lung adenocarcinoma. Recently, a RET (exon 12) rearrangement with FGFR1OP [fibroblast growth factor receptor 1 (FGFR1) oncogene partner] (exon 12) was identified in one chronic myelomonocytic leukemia (CMML) patient. We report the molecular cloning and functional characterization of a novel FGFR1OP (exon 11)-RET (exon 11) gene fusion event (named FGFR1OP-RET), mediated by a reciprocal translocation t(6; 10)(q27; q11), in a patient affected by primary myelofibrosis (PMF) with secondary acute myeloid leukemia (AML). The FGFR1OP-RET fusion protein displayed constitutive tyrosine kinase and transforming activity in NIH3T3 fibroblasts, and induced IL3-independent growth and activation of PI3K/STAT signaling in hematopoietic Ba/F3 cells. FGFR1OP-RET supported cytokine-independent growth, protection from stress and enhanced self-renewal of primary murine hematopoietic progenitor and stem cells in vitro. In vivo, FGFR1OP-RET caused a spectrum of disease phenotypes, with >50% of mice showing a fatal myeloproliferative disorder (MPD). Other phenotypes were leukemia transplantable in secondary recipients, dramatic expansion of the mast cell lineage, and reduction of repopulating activity upon lethal irradiation. In conclusion, FGFR1OP-RET chimeric oncogenes are endowed with leukemogenic potential and associated to myeloid neoplasms (CMML and PMF/AML).
(Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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