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RET fusion genes, BCR-RET and FGFR1OP-RET, are associated with chronic myelomonocytic leukemia, display sensitivity to Sorafenib, an inhibitor of tyrosine-kinase activity and enhance monocytic differentiation

ABSTRACT: Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from point mutations or chimaeric fusion genes, such as BCR ABL1 or JAK2 V617F. We report here for the first time in hematological malignancies, two novel fusion genes involving the TK RET, BCR-RET and FGFR1OP-RET, in chronic myelo monocytic leukemia (CMML) cases. The two RET fusion genes lead to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. We also report that the BCR-RET fusion protein is insensitive to Imatinib but sensitive to Sorafenib in vivo. CMML is an hematopoietic malignancy associated with the frequent activation of the RAS pathway. The RET fusion genes seems to constitutively mimic the same signaling pathway than RAS mutations. Overall, the RET fusion genes behaviors in the monocytic lineage underlie the role of the normal RET TK activity during the physiological monocytic differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE34900 | GEO | 2012/01/06

SECONDARY ACCESSION(S): PRJNA150179

REPOSITORIES: GEO

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Project description:Genomic rearrangements leading to intragenic gene fusion are mainly found in some types of haematopoietic malignancies and sarcomas. Recently they have been described also in carcinomas such as the papillary thyroid histotype (60%-70%) and the Hürthle thyroid tumours (58%). The presence of junction oncogene constitutes an area of exciting research for emerging therapy as targeting the RET-PTC1 fusion oncogene by using small interfering RNA (siRNA) strategies since it is present only in the tumour cells and not in the surrounding normal cells. Therefore, we developed a siRNA against RET-PTC1 junction and assess its efficiency on the human papillary thyroid carcinoma cell line TPC-1 which spontaneously harbours the RET-PTC1 oncogene. The targeted genes are assessed by microarray analysis by comparing the regulated genes by the siRNA_RET-PTC1 vs a siRNA_RET developed on the RET part of the mRNA minus the siRNA_control that contain four mutation within the RET-PTC1 sequence. To test the targeted genes in the TPC-1 cell line that spontaneously harbours RET-PTC1 junction of two siRNAs developed: Within the RET-PTC1 junction, and in the mRNA RET part. A non-specific siRNA harbouring 4 mutations within the RET-PTC1 sequence was used as negative control (siRNA_control). By real-time PCR (Q-RT-PCR) we demonstrated that both siRNAs (siRNA_RET-PTC1 and siRNA_RET) significantly reduce RET mRNA levels of about 85 % in TPC-1 cells. The negative control did not show an effect of RET mRNA levels. Three independent transfections were performed on TPC-1 cells using 5 µl of Lipofectamine 2000 transfection reagent (Invitrogen, Cergy-Pontoise, France) and 50nM of i) siRNA_RET-PTC1 or ii) siRNA_RET or iii) siRNA_control that harbour 4 mutations within its sequence. Total RNAs of untreated cells and transfected cells were purified using the RNA cleanup and concentration kit (QIAGEN, Hilden, Germany) and gathered in 4 pools : 1) TPC-1 harbouring RET-PTC1 ; 2) TPC-1 silenced for RET-PTC1 with siRNA RET-PTC1 ; 3) TPC-1 silenced for siRNA RET ; 4) TPC-1 treated with the siRNA control.

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RET fusion genes, BCR-RET and FGFR1OP-RET, are associated with chronic myelomonocytic leukemia, display sensitivity to Sorafenib, an inhibitor of tyrosine-kinase activity and enhance monocytic differentiation

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