title: Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.
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).
authors: Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy.
authors: Daniela
authors: D
authors: Bossi
authors: Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy.
authors: Francesca
authors: F
authors: Carlomagno
authors: Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy.
authors: Isabella
authors: I
authors: Pallavicini
authors: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors: Giancarlo
authors: G
authors: Pruneri
authors: Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy.
authors: Maurizio
authors: M
authors: Trubia
authors: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors: Paola Rafaniello
authors: PR
authors: Raviele
authors: Department of Biosciences, University of Milan, Milan, Italy.
authors: Alessandra
authors: A
authors: Marinelli
authors: Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy.
authors: Suresh
authors: S
authors: Anaganti
authors: Department of Hematology, A.O. Sant'Andrea, University La Sapienza, Rome, Italy.
authors: Maria Christina
authors: MC
authors: Cox
authors: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors: Giuseppe
authors: G
authors: Viale
authors: Department of Biology and Cellular and Molecular Pathology, University Federico II, Naples, Italy. Electronic address: masantor@unina.it.
authors: Massimo
authors: M
authors: Santoro
authors: 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.
authors: Pier Paolo
authors: PP
authors: Di Fiore
authors: 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.
authors: Saverio
authors: S
authors: Minucci
mesh_terms: D000818:Animals; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics / Q000378:metabolism; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C117597:CEP43 protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: Chromosomal translocation; FGFR1OP-RET; Leukemia; Mast cells; Murine models; Myeloproliferative disorders