Edit ID | Edit Comment | Time | |
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402035 | Update for the myeloid panel | 11/12/2018 3:40 PM |
SETBP1 is a protein which is believed to inhibit PP2A phosphatase activity through SET stabilization. Heterozygous, somatic, missense mutations affecting the SKI homologous region(putative degron region that includes a PEST domain) in exon 4 of SETBP1 have been described in approximately 25% of atypical chronic myelogenous leukemia, up to 17% of secondary acute myeloid leukemia, 10% of unclassifiable myeloproliferative/myelodysplastic syndromes, 5-15% of chronic myelomonocytic leukemia and occasional cases of chronic neutrophilic leukemia. Otherwise, SETPB1 mutations appear to be rare(less than 5%) or absent among cases of primary acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. SETBP1 mutations may be seen together with mutations in other genes such as ASXL1. SETBP1 Gly870Ser mutation has been associated with increased SETBP1 protein, increased SET protein levels, decreased PP2A activity and increased cell proliferation. SETBP1 mutations may be associated with a worse prognosis according to some studies.
SETBP1 encodes a protein which is believed to inhibit PP2A phosphatase activity through SET stabilization. In addition, SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of a network of development genes through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Heterozygous, somatic, missense mutations are predominantly hot-spot mutations within the SKI homologous region in exon 4, which result in the functional loss of the degron motif responsible for the short half-life of the protein. Therefore, these mutations result in an increased half-life and accumulation of the mutated SETBP1, and thus increased inhibition of the oncosupressor PP2A through the SETBP1-SET-PP2A axis. In addition, mutations in SETBP1 potentially deregulate gene transcription mediated by SETBP1. SETBP1 mutations have been described in approximately 25% of atypical chronic myelogenous leukemia, 30% of juvenile myelomonocytic leukemia, 17% of secondary acute myeloid leukemia, 13% of myeloproliferative/myelodysplastic syndrome with ring sideroblasts and thrombocytosis, and 5-15% of chronic myelomonocytic leukemia. SETPB1 mutations appear to be rare (< 5%) or absent among cases of primary acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, myeloproliferative neoplasms and chronic lymphocytic leukemia. SETBP1 mutations may be seen together with mutations in other genes such as ASXL1. SETBP1 mutations are associated with disease progression in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), and unfavorable prognosis in chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, and MDS/MPN with ring sideroblasts associated and thrombocytosis.