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

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

Research output: Contribution to journalArticlepeer-review

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 invitro. Invivo, 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).

Original languageEnglish
Pages (from-to)221-231
Number of pages11
JournalMolecular Oncology
Volume8
Issue number2
DOIs
Publication statusPublished - Mar 2014

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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