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Mol Oncol. 2014 Mar;8(2):221-31. doi: 10.1016/j.molonc.2013.11.004. Epub 2013 Nov 19.

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

Author information

  • 1Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy.
  • 2Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy.
  • 3Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
  • 4Department of Biosciences, University of Milan, Milan, Italy.
  • 5Department of Hematology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy.
  • 6Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy. Electronic address: masantor@unina.it.
  • 7Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy; Department of Scienze della Salute, University of Milan, Via di Rudin√¨ 8, 20122 Milan, Italy; IFOM, FIRC Institute of Molecular Oncology, Milan, Italy. Electronic address: pierpaolo.difiore@ifom.eu.
  • 8Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy. Electronic address: saverio.minucci@ieo.eu.

Abstract

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.

KEYWORDS:

Chromosomal translocation; FGFR1OP-RET; Leukemia; Mast cells; Murine models; Myeloproliferative disorders

PMID:
24315414
[PubMed - indexed for MEDLINE]
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