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Updated: May 5, 2026
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies
Daniela Bossi1, Francesca Carlomagno2, Isabella Pallavicini1
1Department of Experimental Oncology, IEO, European Institute of Oncology, Milan, Italy.
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).
Insights
A novel FGFR1OP-RET fusion gene was identified in myeloproliferative neoplasms. This fusion protein drives leukemogenesis by promoting abnormal cell growth and survival in hematopoietic stem cells.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- The RET receptor tyrosine kinase is a known oncogenic driver in various cancers.
- Previous studies identified RET rearrangements in thyroid and lung cancers, and a RET-FGFR1OP fusion in chronic myelomonocytic leukemia (CMML).
- Primary myelofibrosis (PMF) with secondary acute myeloid leukemia (AML) represents a complex myeloid neoplasm.
Purpose of the Study:
- To identify and functionally characterize novel gene fusions in myeloid neoplasms.
- To investigate the oncogenic potential of the newly identified FGFR1OP-RET fusion.
- To elucidate the molecular mechanisms underlying FGFR1OP-RET-driven hematopoiesis and disease development.
Main Methods:
- Molecular cloning of the FGFR1OP-RET fusion gene from a patient with PMF and secondary AML.
- Functional assays in NIH3T3 fibroblasts and Ba/F3 hematopoietic cells to assess transforming activity and signaling pathway activation (PI3K/STAT).
- In vitro studies using murine hematopoietic progenitor and stem cells to evaluate self-renewal and stress resistance.
- In vivo studies in mice to assess the in vivo oncogenic potential and disease phenotypes.
Main Results:
- A novel FGFR1OP-RET fusion was identified, mediated by a reciprocal translocation t(6;10)(q27;q11).
- The FGFR1OP-RET fusion protein exhibited constitutive tyrosine kinase activity and transforming potential.
- FGFR1OP-RET induced IL3-independent growth, enhanced self-renewal, and stress resistance in hematopoietic cells.
- In vivo, FGFR1OP-RET caused myeloproliferative disorders, transplantable leukemia, mast cell expansion, and impaired stem cell function in mice.
Conclusions:
- The FGFR1OP-RET chimeric oncogene possesses significant leukemogenic potential.
- This fusion is associated with myeloid neoplasms, including CMML and PMF/AML.
- FGFR1OP-RET represents a novel oncogenic driver in hematological malignancies.
