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: Daniela Bossi, Francesca Carlomagno, Isabella Pallavicini, Giancarlo Pruneri, Maurizio Trubia, Paola Rafaniello Raviele, Alessandra Marinelli, Suresh Anaganti, Maria Christina Cox, Giuseppe Viale, Massimo Santoro, Pier Paolo Di Fiore, Saverio Minucci
• Journal: Molecular oncology (Mol Oncol) Vol. 8 Issue 2 Pg. 221-31 (Mar 2014) ISSN: 1878-0261 [Electronic] United States
• PMID: 24315414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• CEP43 protein, human
• Oncogene Proteins, Fusion
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Animals
• Chromosomes, Human, Pair 10 (genetics, metabolism)
• Chromosomes, Human, Pair 6 (genetics, metabolism)
• Hematologic Neoplasms (genetics, metabolism, pathology)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Mice
• NIH 3T3 Cells
• Oncogene Proteins, Fusion (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-ret (genetics, metabolism)
• Translocation, Genetic