Letters to the Editor
1092
Takita, MD, Kohmei Ida, MD, Department of Pediatrics, Graduate
School of Medicine, University of Tokyo, and Kazuko Kudo,
Department of Hematology/Oncology, Shizuoka Children’s Hospital, for providing the JMML samples. We also thank Mrs Chisato
Murata and Miss Sayaka Takeuchi for their excellent technical
assistance. This work was supported by a grant for Cancer
Research, and a grant for Research on Children and Families from
the Ministry of Health, Labor, and Welfare of Japan, a Grant-inAid for Scientific Research (B, C) and Exploratory Research from
the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by a Research grant for Gunma Prefectural
Hospitals.
N Shiba1,2, M Kato3, M-j Park2, M Sanada3, E Ito4,
K Fukushima5, M Sako6, H Arakawa1, S Ogawa3
and Y Hayashi2
1
Department of Pediatrics, Gunma University Graduate
School of Medicine, Gunma, Japan;
2
Department of Hematology/Oncology, Gunma Children’s
Medical Center, Gunma, Japan;
3
Cancer Genomics Project, Graduate School of Medicine,
University of Tokyo, Tokyo, Japan;
4
Department of Pediatrics, Hirosaki University Graduate
School of Medicine, Hirosaki, Japan;
5
Department of Pediatrics, Dokkyo Medical University School
of Medicine, Mibu, Japan and
6
Department of Pediatrics Hematology/Oncology, Osaka City
General Hospital, Osaka, Japan
E-mail: [email protected]
References
1 Niemeyer CM, Kratz CP. Paediatric myelodysplastic syndromes and
juvenile myelomonocytic leukaemia: molecular classification and
treatment options. Br J Haematol 2008; 140: 610–624.
2 Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S et al.
Gain-of-function of mutated C-CBL tumour suppressor in myeloid
neoplasms. Nature 2009; 460: 904–908.
3 Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS,
Szpurka H et al. 250 K single nucleotide polymorphism
array karyotyping identifies acquired uniparental disomy and
homozygous mutations, including novel missense substitutions of
c-Cbl, in myeloid malignancies. Cancer Res 2008; 68: 10349–10357.
4 Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C et al.
Frequent CBL mutations associated with 11q acquired uniparental
disomy in myeloproliferative neoplasms. Blood 2009; 113:
6182–6192.
5 Yamamoto G, Nannya Y, Kato M, Sanada M, Levine RL, Kawamata N
et al. Highly sensitive method for genomewide detection of
allelic composition in nonpaired, primary tumor specimens by
use of affymetrix single-nucleotide-polymorphism genotyping microarrays. Am J Hum Genet 2007; 81: 114–126.
6 Chen Y, Takita J, Hiwatari M, Igarashi T, Hanada R, Kikuchi A et al.
Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and
pediatric hematological malignancies. Genes Chromosomes Cancer
2006; 45: 583–591.
7 Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S
et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 2009; 114: 1859–1863.
8 Thien CB, Langdon WY. Tyrosine kinase activity of the EGF receptor
is enhanced by the expression of oncogenic 70Z-Cbl. Oncogene
1997; 15: 2909–2919.
Trisomy 11: prevalence among 22 403 unique patient cytogenetic studies and clinical
correlates
Leukemia (2010) 24, 1092–1094; doi:10.1038/leu.2010.51;
published online 1 April 2010
Trisomy 11 is a rare cytogenetic abnormality and is yet reported
to be one of the most frequent autosomal trisomies in acute
myeloid leukemia (AML).1 In a Cancer and Leukemia Group B
study, isolated trisomy 11 was identified in 13 cases (0.9%)
among 1496 consecutive adult patients with AML.2 The majority
of the patients with isolated trisomy 11 were older than 60 years
and 46% achieved a complete remission after induction
chemotherapy.2 However, only one patient remained in first
complete remission after undergoing allogeneic bone marrow
transplantation. In a recent Leukemia paper, Wang et al.3
identified 42 cases (0.008%) with trisomy 11 among B5000
patients with myelodysplastic syndrome (MDS) or MDS with
myeloproliferative features. Seventeen of the 42 patients
(median age, 75 years) had trisomy 11 as a sole abnormality
(n ¼ 10) or together with one or two additional abnormalities.
Specific diagnoses in these 17 patients were refractory anemia
with excess of blasts (RAEB)-2 in 8 patients, RAEB-1 in 5,
refractory cytopenia with multilineage dysplasia in 1, therapyrelated MDS in 1 and chronic myelomonocytic leukemia-2 in 1;
bone marrow was not available for review in the remaining 1
patient. The authors compared their trisomy 11 MDS patients
with historical controls and found their survival to be similar to
that of high-risk MDS patients. Accordingly, they concluded that
Leukemia
trisomy 11 should be considered a high-risk cytogenetic
abnormality in MDS.
In the current study, we sought to clarify the prevalence of
trisomy 11 in an unselected series of cytogenetic studies
performed at the Mayo Clinic over the last 20 years and
describe their clinical and pathological features. Between
January 1988 and December 2008, unique patient cytogenetic
studies were performed in 22 403 adults (age X18 years).
Among them, we identified 19 patients (B0.08%) with
abnormalities that included trisomy 11; WHO (World Health
Organization)-defined4 clinical diagnosis at the first sighting of
trisomy 11 was AML in 14 patients and MDS in 5 (Table 1).
Among the former, 10 cases constituted de novo AML and 4
constituted relapsed or secondary AML. Among the five MDS
patients, three had RAEB-2 and two had RAEB-1. Trisomy 11
occurred as a sole abnormality in 10 patients with AML, but in
only one patient with MDS (RAEB-2).
The median age at detection of trisomy 11 in AML was 71
years and in MDS was 67 years (range, 64–86). Median (range)
values in AML included 8.7 g/100 ml (6.5–11.8) for hemoglobin,
6 109/l (1.2–123) for leukocytes and 96 109/l (12–444) for
platelets. The corresponding values in MDS were 9.2 g/100 ml
(8.1–11.3), 1.8 109/l (1.1–3.2) and 129 109/l (78–199),
respectively. Approximately 50% of the AML patients were
exposed to either cytotoxic or radiation therapy before the
detection of trisomy 11 (Table 1). AML transformation was
documented in one patient with RAEB-2 after 23 months of
follow-up. In all the patients with relapsed AML and in one
Letters to the Editor
1093
Table 1
Cytogenetic, clinicopathological and outcome data in 19 patients with trisomy 11
Diagnosis at
the time of trisomy
11 detectiona
Status at last
Time from
follow-up
detection of
trisomy 11 to
last follow-up or
death (months)
Karyotype
Age
(years)/sex
Previous exposure to chemotherapy
or radiotherapy (interval
between exposure and
detection of trisomy 11)
AML, n ¼ 14
AML with maturation
AML with maturation
47,XY,+11[15]/46,XY[5]
47,XY,+11[15]/46,XY[5]
67/M
75/M
19
12
Dead
Dead
AML with maturation
AML with maturation
AML with maturation
47,XX,+11[20]
47,XY,+11[9]/46,XY[11]
47,XX,+11[20]
66/F
76/M
77/F
13
5
3
Dead
Dead
Dead
AML with maturation
47,XX,+11[3]/48,XX,+11,+13[1]/
46,XX[16]
47,XY,+11[2]/
46,XY,del(20)(q11.2)[1]/
48,XY,+4,+8[1]/46,XY[26]
47,XX,+11[11]/46,XX[9]
68/F
None
Radiotherapy after cystectomy for
transitional carcinoma of bladder
(6 years)
None
None
Radiotherapy after total hysterectomy
for endometrial stromal sarcoma
(11 years)
None
72/M
None
16
Dead
69/F
Therapy for breast cancer after
mastectomy: adriamycin and
cyclophosphamide (8 years)
None
None
Hydroxyurea for PMF (2 years)
2
Dead
18
14
2
Alive
NA
Dead
AML with maturation
AML with maturation
AML with maturation
Acute myelomonocytic leukemia
AML with maturation evolved
from PMF
Relapsed AML with maturation
47,XY,+11[9]/46,XY[11]
47,XY,+11[8]/46,XY[12]
47,XX,+11[15]/46,XX[5]
64/M
58/M
78/F
47,XY,+11[17]/
46,XY,del(9)(q13q22)[3]
74/M
Relapsed AML with maturation
47,XX,+11[4]/46,XX[26]
51/F
Relapsed AML with maturation
47,XX,+11[8]/46,XX[7]
74/F
47,XY,+11,idic(Y)(q11.1)[6]/
46,XY[14]
47,XY,+11[20]
47,XY,+11[3]/47,XY,+8[2]/46,XY[25]
47,XY,+11[4]/47,XY,+9[2]/46,XY[24]
47,XY,+11[2]/46,XY,der(1)t(1;11)
(p36.3;q13)[2]/46,XY[36]
MDS, n ¼ 5
RAEB-2
RAEB-2
RAEB-2
RAEB-1
RAEB-1
5.5
0.25
Dead
Dead
Induction therapy: cytarabine,
6-thioguanine; maintenance therapy:
cytarabine, vincristine, 6-thioguanine,
daunorubicin, dexamethasone
(14 years)
Induction therapy: daunorubicin,
cytarabine and 6-thioguanine;
consolidation therapy: etoposide and
cytarabine for 3 courses (2 years)
Induction therapy: adriamycin and
cytarabine (14 years)
11
Dead
3
Dead
72/M
None
24
Dead
86/M
65/M
64/M
68/M
None
None
None
None
13
16
6
12
Dead
Dead
NA
Dead
Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; NA, not available; PMF, primary myelofibrosis; RAEB, refractory
anemia with excess of blasts.
a
According to 2008 WHO classification.
patient with post-myelofibrosis AML, trisomy 11 was not detected
at the time of the initial diagnosis of AML or myelofibrosis. As
outlined in Table 1, the overall outcome after detection of trisomy
11 was dismal although three AML patients achieved complete
remission with induction chemotherapy. One patient with RAEB2 was treated with 5-azacitidine for three cycles without
response. The median survival after detection of trisomy 11 was
15 months for AML and 13 months for MDS.
The current study confirms the rarity of trisomy 11 and its
association with high-risk myeloid malignancies, primarily
AML. Despite our large series of over 22 000 unique patient
cytogenetic studies, we identified only five patients with MDS
and none belonged to the low or intermediate-1 risk category.5
Furthermore, both our study and those of others indicate that
patients with trisomy 11 are older and a substantial proportion
has had previous exposure to chemotherapy or radiation
treatment. These observations, combined with the fact that
internal tandem duplication of the MLL and FLT3 genes
frequently accompany trisomy 11,6 makes it difficult to assign
an independent prognostic weight to trisomy 11. Therefore,
although it is reasonable to conclude that trisomy 11 clusters
with AML and higher-risk MDS, it is both scientifically
inaccurate and practically extraneous to suggest its formal
categorization as a ‘poor’ outcome karyotype in MDS.3
Conflict of interest
The authors declare no conflict of interest.
D Caramazza1, RP Ketterling2,3, RA Knudson2,3,
CA Hanson4, S Siragusa1, A Pardanani5,6 and A Tefferi2
1
Cattedra ed UO di Ematologia, Policlinico Universitario di
Palermo, Palermo, Italy;
2
Division of Cytogenetics, Mayo Clinic, Rochester,
MN, USA;
3
Department of Laboratory Medicine,
Mayo Clinic, Rochester, MN, USA;
4
Division of Hematopathology, Mayo Clinic,
Rochester, MN, USA;
5
Division of Hematology, Mayo Clinic,
Rochester, MN, USA and
6
Department of Medicine, Mayo Clinic, Rochester, MN, USA
E-mail: [email protected]
Leukemia
Letters to the Editor
1094
References
1 Primary, single, autosomal trisomies associated with haematological
disorders. Leuk Res 1992; 16: 841–851.
2 Heinonen K, Mrozek K, Lawrence D, Arthur DC, Pettenati MJ,
Stamberg J et al. Clinical characteristics of patients with
de novo acute myeloid leukaemia and isolated trisomy 11:
a Cancer and Leukemia Group B study. Br J Haematol 1998; 101:
513–520.
3 Wang SA, Jabbar K, Lu G, Chen SS, Galili N, Vega F et al. Trisomy
11 in myelodysplastic syndromes defines a unique group of
disease with aggressive clinicopathologic features. Leukemia,
(in press).
4 Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med
2009; 361: 1872–1885.
5 Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al.
International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.
6 Rege-Cambrin G, Giugliano E, Michaux L, Stul M, Scaravaglio P,
Serra A et al. Trisomy 11 in myeloid malignancies is associated
with internal tandem duplication of both MLL and FLT3 genes.
Haematologica 2005; 90: 262–264.
Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic
syndromes and MDS/myeloproliferative neoplasms
Leukemia (2010) 24, 1094–1096; doi:10.1038/leu.2010.52;
published online 8 April 2010
Acquired somatic mutations affecting the R132 residue of
isocitrate dehydrogenase 1 (IDH1) and the R172 residue of
IDH2 have been initially described in gliomas, mainly in
oligoastrocytic tumors.1 More recently, mutation of the IDH1
gene has been reported in de novo acute myeloid leukemia
(AML).2 The prevalence of IDH1 mutations in de novo AML
ranges between 5–9% of cases. They are strongly associated
with the normal karyotype and are more frequent in patients
with NPM1 mutation. IDH1 mutations have no impact on
event-free survival in AML patients, except that they have an
unfavorable effect on event-free survival in those with intermediate-risk karyotype.3,4 The fourth exon of both IDH1 and
IDH2 genes encodes three arginine residues (R100, R109 and
R132 in IDH1 and R140, R149 and R172 in IDH2) that are
important for the activity of the proteins.5
Table 1
Patient
number
6
62
30
31
71
47
187
257
273
723
178
209
142
53
140
94
107
Here we have analyzed the sequence of the fourth exon of
IDH1 and IDH2 genes established from the bone marrow DNA
of 100 cases of myelodysplastic syndrome (MDS) including all
subtypes of the WHO 2008 classification, 90 cases of MDS/
myeloproliferative neoplasm (MPN), including 88 cases of
chronic myelomonocytic leukemia and 2 cases of refractory
anemia with ringed sideroblast and thrombocytosis, and 41
cases of AML post-MDS and AML post-MDS/MPN, referred to
as secondary AML (sAML). To identify associations between
molecular events, we also established the TET2 and JAK2 status
of the samples.
Out of 231 cases, mutations in IDH1 or IDH2 genes were
identified in 5% (n ¼ 5) of MDS, in 8.8% (n ¼ 8) of MDS/MPN
and in 9.7% (n ¼ 4) of sAML cases. The frequencies were not
statistically different between the three groups. The characteristics of patients with a mutation in IDH genes are summarized
in Table 1. IDH1 and IDH2 mutations were always heterozygous and were mutually exclusive. Among the 17 patients
with IDH gene mutations, 11 presented with IDH2 R140Q,
Mutational status of 17 MDS, MDS/MPN or sAML patients with IDH1 or IDH2 substitutions
WHO
Age at diagnosis
(years)
Karyotype
RAEB 1
RAEB 1
RAEB 1
RAEB 1
RARS
CMML2
CMML1
CMML1
CMML1
CMML1
CMML1
CMML2
RARS-T
sAML
sAML
sAML
sAML
74
83
73
69
72
77
76
71
76
83
88
73
80
66
59
78
64
46, XY
46, XX
46, XY
46, XY
46, XX
46, XY
46, XY
46, XX
46, XY
46, XY
46, XY, del(20)(q11q13)
46, XY
46, XX
46, XX
46, XY
47, XY, +8
48, XY, +8, +8
IDH mutation
IDH1
IDH1
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH2
IDH1
IDH1
IDH2
IDH2
R132G
R132L
R140Q
R140Q
R140Q
R140Q
R140Q
R140Q
R140Q
R140Q
R140Q
R172K
R140L
R132C
R132C
R140Q
R140Q
TET2 status
JAK2
status
wt
wt
Q1834 FS
wt
wt
wt
wt
wt
G1361S
wt
wt
Deletion
wt
Y1560 FS
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
V617F
wt
wt
wt
wt
Abbreviations: CMML, chronic myelomonocytic leukemia; IDH, isocitrate dehydrogenase; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; RAEB, refractory anemia with excess blasts; RARS-T, refractory anemia with ringed sideroblast and thrombocytosis; sAML,
secondary acute myeloid leukemia; wt, wild type.
TET2 gene was sequenced as described previously in all samples8 and search for JAK2 V617F mutation was performed using the JAK2
Mutascreen Kit (Ipsogen, Marseille, France). Patient 209 was analyzed both at diagnosis of CMML and after evolution to an AML with a complex
karyotype (48, XY, +X or mar1, +der(11) or mar2[7]/46, XY[18]). One case of TET2 deletion was identified by SNP array.
Leukemia