Open AccessFunctional characterization of a novel FGFR1OP‐RET rearrangement in hematopoietic malignancies
Author(s) -
Bossi Daniela,
Carlomagno Francesca,
Pallavicini Isabella,
Pruneri Giancarlo,
Trubia Maurizio,
Raviele Paola Rafaniello,
Marinelli Alessandra,
Anaganti Suresh,
Cox Maria Christina,
Viale Giuseppe,
Santoro Massimo,
Di Fiore Pier Paolo,
Minucci Saverio
Publication year - 2014
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2013.11.004
Subject(s) - cancer research , biology , myeloid leukemia , tyrosine kinase , myelofibrosis , myeloid , ectodomain , haematopoiesis , fusion gene , neuroblastoma ras viral oncogene homolog , receptor tyrosine kinase , leukemia , juvenile myelomonocytic leukemia , microbiology and biotechnology , stem cell , immunology , mutation , receptor , signal transduction , genetics , bone marrow , kras , gene
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).