SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms.

Emiliano Fabiani, Giulia Falconi, Luana Fianchi, Marianna Criscuolo, Giuseppe Leone, Maria Teresa Voso

Research output: Contribution to journalArticle

11 Citations (Scopus)


Therapy-related myeloid neoplasms (t-MN) are myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) developing in patients treated with radiotherapy and/or chemotherapy for cancer or autoimmune diseases. Cytotoxic therapy may induce chromosomal alteration and genetic mutations in hematopoietic progenitors leading to leukemogenesis in susceptible subjects. t-MNs are characterized by high incidence of complex karyotypes and frequent monosomies and/or deletions of chromosomes 7 and/or 5,1 whereas the recently identified mutations of epigenetic regulators and of the spliceosome machinery are rare, with the exception of SRSF2.2,3 Recently, new sequencing technologies have enabled large screening of somatic mutations in myeloid malignancies, leading to the discovery of new hot spot mutations in genes candidate for leukemic transformation. Among these, SET binding protein 1 (SETBP1) has been reported as frequently mutated in chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), secondary acute myeloid leukemia (s-AML) and in distinct subgroups of primary myelodysplastic syndromes (MDS), such as refractory anemia with excess of blasts (RAEB1 and RAEB2).4-10 SETBP1 germ-line mutations are responsible for the Schinzel-Giedion syndrome (SGS), originally identified by Albert Schinzel and Andreas Giedion in 1978. It is a congenital disease characterized by a higher prevalence of tumors, severe mid-face hypoplasia, congenital heart defect and skeletal anomalies.11 The SETBP1 gene is localized on chromosome 18q21.1 and the missense mutations are predominantly located in the SKI-homologous region, mainly between codon 858 and 871. Makishima et al. have previously shown a significant association between SETBP1 mutations and −7/del(7q) abnormalities (15 of 72; P=0.01) in a large cohort of 727 patients with myeloid malignancies.4 SETBP1 mutations were more frequent in AML evolving from a previous MDS, and CMML patients (19 of 113 cases, 16.8%, and 22 of 152 cases, 14.5%, respectively), whereas they were less frequent in de novo AML (1 of 145 cases, <1%). Similarly, Fernandez-Mercado et al., screening a population of 328 patients with myeloid disorders, found 14 SETBP1 mutations (4.3%), 7 of which in patients with -7/del(7q) (7 of 19, 36.8%).7 Moreover, Hou et al. found 14 SEPBP1 mutations in a cohort of 430 (3.3%) MDS patients (FAB classification), in particular in association to monosomy 7 (20%), and a significantly higher incidence of concurrent ASXL1, EZH2 and SRSF2 mutations.8 To date, little is known regarding prevalence, clinical and prognostic role of SETBP1 mutations in t-MN. Since t-MN are characterized by high prevalence of chromosome 7 alterations and SRSF2 mutations, the aim of our study was to determine the frequency of SETBP1 mutations in a cohort of 106 patients affected by t-MN, diagnosed at our institution between January 1994 and September 2013. Patients had developed a t-MN at a median of six years (range 0.1-32 years) from treatment of the primary disease. Median bone marrow (BM) blasts were 18 (range 1-100). Karyotype was abnormal in 52 of 81 (64.2%) patients with available karyotype. Chromosome 7 alterations were present in 16 of 81 (19.7%) patients. Patients’ main clinical characteristics are described in Table 1. The study was approved by our Institutional Review Board and was conducted according to good clinical and laboratory practice rules and the principles of the Declaration of Helsinki. Mononuclear cells (MNCs) were separated from patients’ BM at the time of initial diagnosis by Ficoll gradient centrifugation using Lympholyte-H (Cedarlane, Ontario, Canada). DNA was extracted using a QIAamp DNA Mini Kit (Qiagen Srl., Milan, Italy), following the manufacturer’s instructions. Detection of SETBP1 mutations was performed by Sanger sequ
Original languageEnglish
Pages (from-to)152-153
Number of pages2
Publication statusPublished - 2014
Externally publishedYes


  • SETBP1 mutations
  • therapy-related myeloid neoplasms


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