TY - JOUR
T1 - SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms.
AU - Fabiani, Emiliano
AU - Falconi, Giulia
AU - Fianchi, Luana
AU - Criscuolo, Marianna
AU - Leone, Giuseppe
AU - Voso, Maria Teresa
PY - 2014
Y1 - 2014
N2 - 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
AB - 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
KW - SETBP1 mutations
KW - therapy-related myeloid neoplasms
KW - SETBP1 mutations
KW - therapy-related myeloid neoplasms
UR - http://hdl.handle.net/10807/60303
U2 - 10.3324/haematol.2014.108159
DO - 10.3324/haematol.2014.108159
M3 - Article
SN - 0390-6078
VL - 99
SP - 152
EP - 153
JO - Haematologica
JF - Haematologica
ER -