Somatic SETBP1 mutations in myeloid malignancies

Makishima, Hideki; Yoshida, Kenichi; Nguyen, Nhu; Przychodzen, Bartlomiej; Sanada, Masashi; Okuno, Yusuke; Ng, Kwok Peng; Gudmundsson, Kristbjorn O.; Vishwakarma, Bandana Ajay; Jerez, Andrés; Gómez-Seguí, Inés; Takahashi, Mariko; Shiraishi, Yuichi; Nagata, Yasunobu; Guinta, Kathryn; Mori, Hiraku; Sekeres, Mikkael A.; Chiba, Kenichi; Tanaka, Hiroko; Muramatsu, Hideki; Sakaguchi, Hirotoshi; Paquette, Ronald; McDevitt, Michael A.; Kojima, Seiji; Saunthararajah, Yogen; Miyano, Satoru; Shih, Lee‐Yung; Du, Yang; Ogawa, Seishi; Maciejewski, Jaroslaw P.

doi:10.1038/ng.2696

Cited by 225 publications

(268 citation statements)

References 47 publications

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“…ASXL1 mutations are frequent (57%) and independently predict of a shortened OS in CNL as has been observed in other myeloid malignancies [11][12][13][14]. Although the presence of mutated SETBP1 was not an independent predictor of overall survival in this study as described in other chronic myeloid neoplasms in which it carries a poor prognosis and is acquired during leukemic evolution, both patients with blastic transformation were SETBP1-mutated [15][16][17]. In conclusion, this study provides information on the natural history of CSF3R-mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival.…”

Section: Resultscontrasting

confidence: 41%

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

et al. 2015

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*Colony stimulating factor 3 receptor gene (CSF3R) mutations have recently been associated with chronic neutrophilic leukemia (CNL). Fourteen patients with CSF3R-mutated CNL (median age 67 years; 57% males) were screened for additional mutations; 8 (57%) and 5 (38%) harbored an ASXL1 and/or SETBP1 mutation (two patients expressed both), respectively. Two patients developed blastic transformation, both SETBP1-mutated and ASXL1-unmutated, whereas two other cases evolved into chronic myelomonocytic leukemia (CMML), both ASXL1-mutated and SETBP1-unmutated. Median survival was 23.2 months (10 deaths documented). On multivariable analysis mutated ASXL1 (P 5 0.009; HR 19.6, 95% CI 2.1-184.1) and thrombocytopenia (P 5 0.005; HR 28.8, 95% CI 2.8-298.2) were independently predictive of shortened survival. This study provides information on the natural history of CSF3R-mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival. The study also suggests pathogenetic roles for SETBP1 and ASXL1 mutations in disease evolution into blast phase disease and CMML, respectively.

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Section: Resultscontrasting

confidence: 41%

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

et al. 2015

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“…Somatic SETBP1 mutations are seen in patients with myeloid neoplasms and are relatively frequent in atypical CML ( 24%) and in CMML ( 15-20%) [11,[17][18][19] These mutations most commonly (>90%) occur in codons 858-871 and are similar to the germline mutations seen in the Schinzel-Gideon syndrome [18]. In atypical CML, SETBP1 mutations result in a proliferative phenotype and negatively impact OS [18].…”

Section: Discussionmentioning

confidence: 98%

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had 1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n 5 82), anemia (P 5 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P 5.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n 5 48), univariate analysis showed association between poor survival and presence of SETBP1 (P 5 0.04) or ASXL1 (P 5 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P 5 0.04); the number of concurrent mutations did not provide additional prognostication (P 5 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high ( 2 points), with median survivals of 80, 42 and 11 months respectively (P 5 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutationenhanced prognostic model.

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“…An association with high leukocyte counts and an independent detrimental effect on prognosis was confirmed in most but not all series. A more recent study, through the analysis of serially collected samples of patients with these myeloid malignancies indicated that these somatic SETBP1 mutations were acquired during leukemic evolution [71]. With regards to CNL, Piazzi noted that one of four cases of CNL carried the SETBP1 mutation and Pardanani et al reported the prevalence of SETBPI mutations to be 33% in WHO-defined CNL cases, all four of whom co-expressed the CSF3RT618I mutation [2].…”

Section: Setbp1 Mutations In Cnlmentioning

confidence: 99%

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

Elliott

Tefferi

2016

American J Hematol

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Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 109/L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R. The clinical presentation, disease course and prognosis of CSF‐R mutated CNL have been recently outlined. Co‐operative mutations in SETBP1 and ASXL1 appear to be of prognostic significance and correlate with disease progression. Advances in the understanding of the molecular pathogenesis of CNL, have not yet fully translated into satisfactory therapeutic strategies, but the foundations for these are strengthening. Am. J. Hematol. 91:342–349, 2016. © 2015 Wiley Periodicals, Inc.

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Somatic SETBP1 mutations in myeloid malignancies

Cited by 225 publications

References 47 publications

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

ASXL1 mutations are frequent and prognostically detrimental in CSF3R‐mutated chronic neutrophilic leukemia

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

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