FGFR1 is fused to the centrosome-associated proteinCEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33)

Abstract

The hallmark of the 8p12 stem cell myeloproliferative disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family.FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion betweenFGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm.

The newly found functions of MTOC in immunological response

“…[5]). Interestingly, the stem cell myeloproliferative disorder, which eventually leads to acute myeloid leukemia and in which hallmarks are T cell or B cell lymphoblastic lymphoma, eosinophila, and myeloid hyperplasia, is caused by a translocation between chromosomes containing the FGFR1 gene and CEP110, resulting in [10,20] the synthesis of CEP110-FGFR1 fusion protein [33]. Recent proteomic studies and super-resolution microscopy have identified the protein components of distal appendages, including CEP164, CEP89 (ccdc123), CEP83 (ccdc41), sodium channel and clathrin linker 1, Fas (TNFRSF6) Binding Factor 1, and CCDC123 (Cep123) in RPE-1, murine inner medullary collecting duct (IMCD3) cells, and the KE37 human T lymphoblastic cell line [23,34], and showed that in ciliated cells, the distal appendages promote membrane docking of the centriole via the function of the CEP83 protein [23].…”

Phosphorylation of the SSBP2 and ABL proteins by the ZNF198‐FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide‐specific MS

“…Our previous studies had suggested that the ZNF198/FGFR1 kinase was autophosphorylated on the ZNF198 moiety present 9,[3979][3980][3981][3982][3983][3984][3985][3986][3987][3988] in the fusion kinase [14]. Analysis of the phosphorylated peptides in this series of cell lines demonstrates that phosphorylation of ZNF198 was not identified in the parental 293 cells, or in those clones over expressing FGFR1, arguing against phosphorylation of the endogenous ZNF198 protein.…”

“…The fusion of the zinc finger domain of the ZNF198 gene with the kinase domain of the fibroblast growth factor receptor-1 (FGFR1) gene was originally defined [1][2][3][4] in an atypical myeloproliferative disease with poor prognosis [1-3, 5, 6]. Since then, variant translocations have been described [7][8][9][10][11][12][13] where, although the partner gene fused with FGFR1 is different, in all cases analyzed so far, the specific partner gene is anticipated to facilitate dimerization of the FGFR1 kinase domain resulting in its constitutive activation [14][15][16]. The chimeric kinase protein, unlike FGFR1, is no longer tethered to the cytoplasmic membrane but resides predominantly in the cytoplasm [14,17] and acts as a constitutive tyrosine kinase.…”

Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement

“…Besides "classical" myeloproliferative neoplasms (MPN), the World Health Organization 2016 classification of tumors of hematopoietic and lymphoid tissues/myeloid neoplasms and acute leukemia incorporates uncommon MPN variants with distinct genetic abnormalities as "myeloid/lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1" [1]. Within these, the subset of "8p11 (eight-p-eleven) myeloproliferative syndromes" (EMS) is defined as acquired hematopoietic stem cell disorders characterized by reciprocal translocation of the FGFR1 gene on chromosome 8p11 to at least three different partner genes at chromosomal regions 6q27, 13q12, or 9q33 [2,3]. The CEP110-FGFR1 fusion translates into a protein that acts as a constitutively active oncogenic tyrosine kinase [4].…”

“…EMS may manifest with concomitant lymphoblastic lymphoma and frequently transforms into acute myeloid leukemia (AML) [5]. Since the first description of the translocation t(8;9)(p11q33) in 1983 [6] and the identification of the resulting CEP110-FGFR1 fusion in 2000 [3], to our knowledge, only 14 EMS patients with this fusion have been reported. Today, this disease subgroup is considered refractory to tyrosine kinase inhibitors (TKI) and is thus afflicted with a particularly poor prognosis [1].…”