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Ref Type Journal Article
PMID (23832012)
Authors Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, Gomez-Segui I, Takahashi M, Shiraishi Y, Nagata Y, Guinta K, Mori H, Sekeres MA, Chiba K, Tanaka H, Muramatsu H, Sakaguchi H, Paquette RL, McDevitt MA, Kojima S, Saunthararajah Y, Miyano S, Shih LY, Du Y, Ogawa S, Maciejewski JP
Title Somatic SETBP1 mutations in myeloid malignancies.
Journal Nature genetics
Vol 45
Issue 8
Date 2013 Aug
Abstract Text Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS), were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology. Mutant cases were associated with advanced age and monosomy 7/deletion 7q (-7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SETBP1 D868N missense gain of function SETBP1 D868N lies within the SKI homologous region of the Setbp1 protein (PMID: 23222956). D868N confers a gain of function to the Setbp1 protein, as demonstrated by increased Setbp1 protein stability, enhanced cell proliferation, is transforming in culture (PMID: 23832012, PMID: 28346496), and when in combination with Asxl1 mutations, D868N increases cell transformation in cell culture and xenograft models through increased PP2A inhibition (PMID: 25306901).
SETBP1 I871T missense gain of function SETBP1 I871T lies within the SKI homologous region of the Setbp1 protein (PMID: 23222956). I871T results in increased Setbp1 protein stability, enhanced cell proliferation, and is transforming in culture (PMID: 23832012, PMID: 28346496).
TET2 G1288S missense unknown TET2 G1288S does not lie within any known functional domains of the Tet2 protein ( G1288S has been identified in sequencing studies (PMID: 21828143, PMID: 26437031, PMID: 23832012), but has not been biochemically characterized and therefore, its effect on Tet2 protein function is unknown (PubMed, Mar 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SETBP1 mutant myelodysplastic syndrome not applicable N/A Clinical Study Prognostic In clinical analyses, mutations in SETBP1 were associated with poor prognosis in patients with myelodysplastic syndrome (PMID: 28447248, PMID: 28158286, PMID: 24127063, PMID: 23889083, PMID: 23832012). 23889083 24127063 28447248 23832012 28158286
SETBP1 mutant chronic myelomonocytic leukemia not applicable N/A Clinical Study Prognostic In clinical analyses, mutations in SETBP1 were associated with poor prognosis in patients with chronic myelomonocytic leukemia (PMID: 29225884, PMID: 28158286, PMID: 28209919, PMID: 23558523, PMID: 23832012). 29225884 28209919 23832012 23558523 28158286
SETBP1 mutant myelodysplastic/myeloproliferative neoplasm not applicable N/A Preclinical Emerging In a preclinical study, SETPB1 missense mutations conferred a predicted gain-of-function, resulting in transformation of murine myeloid progenitors and increased Pp2ac phosphorylation compared to wild-type SETBP1 in culture, suggesting that Setbp1 may serve as a potential therapeutic target (PMID: 23832012). 23832012