Alternative titles; symbols
HGNC Approved Gene Symbol: FES
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38): 15:90,884,504-90,895,776 (from NCBI)
The FES protooncogene encodes a cytoplasmic protein tyrosine kinase implicated in growth factor and cytokine receptor signaling. It is involved myelopoiesis and plays a role in regulating the innate immune response (Zirngibl et al., 2002).
Wong-Staal et al. (1981) identified human DNA sequences homologous to cloned DNA fragments containing the oncogenic nucleic acid sequences of a type C mammalian retrovirus, the Snyder-Theilen strain of feline sarcoma virus (FeSV). Non-onc intervening sequences were present in the human counterpart.
The FES gene was mapped to chromosome 15 (Dalla-Favera et al., 1982). Heisterkamp et al. (1982) also assigned the FES gene to the long arm of chromosome 15. This may have relevance to leukemogenesis in acute promyelocytic leukemia (APL), which shows a translocation between chromosomes 15 and 17 (15q+, 17q-).
By in situ hybridization to germline chromosomes, Jhanwar et al. (1984) assigned FES to chromosome 15q26.1, a site distal to the breakpoint in the translocation commonly seen in acute promyelocytic leukemia, t(15;17)(q24;q22).
By FISH, Mathew et al. (1993) mapped the FES gene to chromosome 15q26.1.
The t(15q+;17q-) of acute promyelocytic leukemia came to light at the First International Workshop on Chromosomes in Leukemia in Helsinki in 1977 and was confirmed by many workers (Rowley et al., 1977; Kondo and Sasaki, 1979). Studying 4 cases of APL, Hagemeijer et al. (1982) defined the breakpoints of the 15;17 translocation as 15q2200 and 17q12. In the 15;17 translocation of acute promyelocytic leukemia, the thymidine kinase locus is on the part of 17q translocated to chromosome 15 (Durnam et al., 1984). Studying somatic cell hybrids constructed between a thymidine kinase-deficient mouse cell line and blood leukocytes from a patient with acute promyelocytic leukemia showing the characteristic 15q+;17q-translocation, Sheer et al. (1983) showed that the FES gene was not present in a hybrid cell showing the 15q+ translocation and little other human chromosomal material. Therefore, FES had been translocated to the 17q- chromosome. B2M (109700) is on 15q+, probably near the breakpoint; this could be relevant to the malignant process. MPI (154550) and PKM2 (179050), like FES, are distal to the breakpoint. The breakpoint on 17 is proximal to the TK and GALK loci; these genes are translocated to 15q+.
In all of 27 patients with acute promyelocytic leukemia, including 4 with the microgranular variant, Larson et al. (1984) found a specific translocation: t(15;17)(q22;q21.1). The FES oncogene is located on 15q25-q26 and the ERBA oncogene on chromosome 17p11-q21. The relation of the translocation to either of these 2 oncogenes in the causation of neoplasia is problematic.
Zirngibl et al. (2002) generated Fes-deficient mice by deleting sequences encoding the kinase domain in the 3-prime region of the gene. This strategy avoided simultaneous disruption of the furin gene (PACE; 136950), which is located immediately upstream of FES. The mice were healthy, viable, and fertile, but had minor defects in hemopoietic homeostasis, such as slightly reduced numbers of myeloid progenitors and circulating mature myeloid cells and increased circulating erythrocytes. Expression of hemopoietic cytokines and activation of Stat3 (102582) and Stat5a (601511) were normal in the mutant mice. Challenge with lipopolysaccharide resulted in reduced survival compared with wildtype mice. Crossing Fes -/- mice with mice expressing a human FES transgene restored the normal phenotype. Zirngibl et al. (2002) concluded that FES has a role in regulating the innate immune response.
A useful general discussion of cellular transforming genes was provided by Cooper (1982). Fourteen transforming genes of acute transforming retroviruses, including fes, were tabulated. Transforming genes activated in human neoplastic cells had been identified in the following human neoplasms: bladder carcinoma (3 tumors), lung carcinoma (4 tumors), mammary carcinoma (1), colon carcinoma (2), promyelocytic leukemia (1), neuroblastoma (1), pre-B lymphocyte neoplasm (4), B-cell lymphoma (6), plasmacytoma/myeloma (2), T-cell lymphoma (1), mature T-helper cell neoplasm (1), and sarcoma (1). Cooper (1982) concluded 'that oncogenesis can involve dominant genetic alterations resulting in activation of cellular transforming genes.' The same genes are activated in independent neoplasms of the same cell type. The finding that specific transforming genes are activated in neoplasms corresponding to discrete stages of lymphocyte differentiation suggests that the transforming genes activated in neoplasms are closely related to the state of normal differentiation exhibited by the neoplastic cells.
Cooper, G. M. Cellular transforming genes. Science 217: 801-806, 1982. [PubMed: 6285471] [Full Text: https://doi.org/10.1126/science.6285471]
Dalla-Favera, R., Franchini, G., Martinotti, S., Wong-Staal, F., Gallo, R. C., Croce, C. M. Chromosomal assignment of the human homologues of feline sarcoma virus and avian myeloblastosis virus onc genes. Proc. Nat. Acad. Sci. 79: 4714-4717, 1982. [PubMed: 6289315] [Full Text: https://doi.org/10.1073/pnas.79.15.4714]
Durnam, D. M., Myerson, D., McDougall, J. K., Gelinas, R. E. Analysis of the t(15;17) specifically associated with acute promyelocytic leukemia.(Abstract) Cytogenet. Cell Genet. 37: 458 only, 1984.
Hagemeijer, A., Lowenberg, B., Abels, J. Analysis of the breakpoints in translocation (15;17) observed in 4 patients with acute promyelocytic leukemia. Hum. Genet. 61: 223-227, 1982.
Hampe, A., Laprevotte, I., Galibert, F., Fedele, L. A., Sherr, C. J. Nucleotide sequences of feline retroviral oncogenes (v-fes) provide evidence for a family of tyrosine-specific protein kinase genes. Cell 30: 775-785, 1982. [PubMed: 6183005] [Full Text: https://doi.org/10.1016/0092-8674(82)90282-3]
Heisterkamp, N., Groffen, J., Stephenson, J. R., Spurr, N. K., Goodfellow, P. N., Solomon, E., Carritt, B., Bodmer, W. F. Chromosomal localization of human cellular homologues of two viral oncogenes. Nature 299: 747-749, 1982. [PubMed: 7121606] [Full Text: https://doi.org/10.1038/299747a0]
Jhanwar, S. C., Neel, B. G., Hayward, W. S., Chaganti, R. S. K. Localization of the cellular oncogenes ABL, SIS, and FES on human germ-line chromosomes. Cytogenet. Cell Genet. 38: 73-75, 1984. [PubMed: 6323103] [Full Text: https://doi.org/10.1159/000132033]
Kondo, K., Sasaki, M. Cytogenetic studies of four cases of acute promyelocytic leukemia (APL). Cancer Genet. Cytogenet. 1: 131-138, 1979.
Larson, R. A., Kondo, K., Vardiman, J. W., Butler, A. E., Golomb, H. M., Rowley, J. D. Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am. J. Med. 76: 827-841, 1984. [PubMed: 6586073] [Full Text: https://doi.org/10.1016/0002-9343(84)90994-x]
Mathew, S., Murty, V. V. V. S., German, J., Chaganti, R. S. K. Confirmation of 15q26.1 as the site of the FES protooncogene by fluorescence in situ hybridization. Cytogenet. Cell Genet. 63: 33-34, 1993. [PubMed: 8449035] [Full Text: https://doi.org/10.1159/000133496]
Roebroek, A. J. M., Schalken, J. A., Verbeek, J. S., Van den Ouweland, A. M. W., Onnekink, C., Bloemers, H. P. J., Van de Ven, W. J. M. The structure of the human c-fes/fps proto-oncogene. EMBO J. 4: 2897-2903, 1985. [PubMed: 4065096] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb04020.x]
Rowley, J. D., Golomb, H. M., Dougherty, C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. (Letter) Lancet 309: 549-550, 1977. Note: Originally Volume I. [PubMed: 65649] [Full Text: https://doi.org/10.1016/s0140-6736(77)91415-5]
Rowley, J. D., Golomb, H. M., Vardiman, J., Fukuhara, S., Dougherty, C., Potter, D. Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia. Int. J. Cancer 20: 869-872, 1977. [PubMed: 271143] [Full Text: https://doi.org/10.1002/ijc.2910200608]
Sheer, D., Hiorns, L. R., Stanley, K. F., Goodfellow, P. N., Swallow, D. M., Povey, S., Heisterkamp, N., Groffen, J., Stephenson, J. R., Solomon, E. Genetic analysis of the 15;17 chromosome translocation associated with acute promyelocytic leukemia. Proc. Nat. Acad. Sci. 80: 5007-5011, 1983. [PubMed: 6576373] [Full Text: https://doi.org/10.1073/pnas.80.16.5007]
Sodroski, J. G., Goh, W. C., Haseltine, W. A. Transforming potential of a human protooncogene (c-fps/fes) locus. Proc. Nat. Acad. Sci. 81: 3039-3043, 1984. [PubMed: 6328490] [Full Text: https://doi.org/10.1073/pnas.81.10.3039]
Wong-Staal, F., Dalla-Favera, R., Franchini, G., Gelmann, E. P., Gallo, R. C. Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses. Science 213: 226-228, 1981. [PubMed: 6264598] [Full Text: https://doi.org/10.1126/science.6264598]
Zirngibl, R. A., Senis, Y., Greer, P. A. Enhanced endotoxin sensitivity in Fps/Fes-null mice with minimal defects in hematopoietic homeostasis. Molec. Cell. Biol. 22: 2472-2486, 2002. [PubMed: 11909942] [Full Text: https://doi.org/10.1128/MCB.22.8.2472-2486.2002]