Key Points

  • Specific gene mutation combinations correlate with morphologic MDS/MPN subtypes and help elucidate the heterogeneity in these neoplasms.

  • Patients with MDS/MPN-U display different molecular profiles that mimic the ones observed in other MDS/MPN subtypes.

Abstract

More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adults with MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 119), atypical chronic myeloid leukemia (aCML; n = 71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 71), and MDS/MPN unclassifiable (MDS/MPN-U; n = 106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that were associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDSs/MPNs (eg, TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML, and SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN subtypes, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.

REFERENCES

REFERENCES
1.
Swerdlow
SH
,
Campo
E
,
Harris
NL
, et al
.
WHO classification of tumours of haematopoietic and lymphoid tissues
.
Lyon, France
:
IARC
;
2017
.
2.
Itzykson
R
,
Kosmider
O
,
Renneville
A
, et al
.
Prognostic score including gene mutations in chronic myelomonocytic leukemia
.
J Clin Oncol
.
2013
;
31
(
19
):
2428
-
2436
.
3.
Jeromin
S
,
Haferlach
T
,
Weissmann
S
, et al
.
Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations
.
Haematologica
.
2015
;
100
(
4
):
e125
-
e127
.
4.
Patnaik
MM
,
Barraco
D
,
Lasho
TL
, et al
.
Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia
.
Am J Hematol
.
2017
;
92
(
6
):
542
-
548
.
5.
Bose
P
,
Nazha
A
,
Komrokji
RS
, et al
.
Mutational landscape of myelodysplastic/myeloproliferative neoplasm-unclassifiable
.
Blood
.
2018
;
132
(
19
):
2100
-
2103
.
6.
Elena
C
,
Gallì
A
,
Such
E
, et al
.
Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia
.
Blood
.
2016
;
128
(
10
):
1408
-
1417
.
7.
Awada
H
,
Nagata
Y
,
Goyal
A
, et al
.
Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia
.
Blood Adv
.
2019
;
3
(
3
):
339
-
349
.
8.
Meggendorfer
M
,
Roller
A
,
Haferlach
T
, et al
.
SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML)
.
Blood
.
2012
;
120
(
15
):
3080
-
3088
.
9.
Patnaik
MM
,
Itzykson
R
,
Lasho
TL
, et al
.
ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients
.
Leukemia
.
2014
;
28
(
11
):
2206
-
2212
.
10.
Piazza
R
,
Valletta
S
,
Winkelmann
N
, et al
.
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia
.
Nat Genet
.
2013
;
45
(
1
):
18
-
24
.
11.
Meggendorfer
M
,
Bacher
U
,
Alpermann
T
, et al
.
SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations
.
Leukemia
.
2013
;
27
(
9
):
1852
-
1860
.
12.
Broséus
J
,
Alpermann
T
,
Wulfert
M
, et al;
MPN and MPNr-EuroNet (COST Action BM0902)
.
Age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis
.
Leukemia
.
2013
;
27
(
9
):
1826
-
1831
.
13.
Patnaik
MM
,
Lasho
TL
,
Finke
CM
, et al
.
Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing
.
Am J Hematol
.
2016
;
91
(
5
):
492
-
498
.
14.
Raczy
C
,
Petrovski
R
,
Saunders
CT
, et al
.
Isaac: ultra-fast whole-genome secondary analysis on Illumina sequencing platforms
.
Bioinformatics
.
2013
;
29
(
16
):
2041
-
2043
.
15.
Kim
S
,
Scheffler
K
,
Halpern
AL
, et al
.
Strelka2: fast and accurate calling of germline and somatic variants
.
Nat Methods
.
2018
;
15
(
8
):
591
-
594
.
16.
McLaren
W
,
Gil
L
,
Hunt
SE
, et al
.
The Ensembl Variant Effect Predictor
.
Genome Biol
.
2016
;
17
(
1
):
122
.
17.
Roller
E
,
Ivakhno
S
,
Lee
S
,
Royce
T
,
Tanner
S
.
Canvas: versatile and scalable detection of copy number variants
.
Bioinformatics
.
2016
;
32
(
15
):
2375
-
2377
.
18.
Hirsch
CM
,
Nazha
A
,
Kneen
K
, et al
.
Consequences of mutant TET2 on clonality and subclonal hierarchy
.
Leukemia
.
2018
;
32
(
8
):
1751
-
1761
.
19.
Abdel-Wahab
O
,
Pardanani
A
,
Patel
J
, et al
.
Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms
.
Leukemia
.
2011
;
25
(
7
):
1200
-
1202
.
20.
Yoshida
K
,
Sanada
M
,
Shiraishi
Y
, et al
.
Frequent pathway mutations of splicing machinery in myelodysplasia
.
Nature
.
2011
;
478
(
7367
):
64
-
69
.
21.
Papaemmanuil
E
,
Gerstung
M
,
Malcovati
L
, et al;
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
.
Clinical and biological implications of driver mutations in myelodysplastic syndromes
.
Blood
.
2013
;
122
(
22
):
3616
-
3627, quiz 3699
.
22.
Haferlach
T
,
Nagata
Y
,
Grossmann
V
, et al
.
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
.
Leukemia
.
2014
;
28
(
2
):
241
-
247
.
23.
Haase
D
,
Stevenson
KE
,
Neuberg
D
, et al;
International Working Group for MDS Molecular Prognostic Committee
.
TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups
.
Leukemia
.
2019
;
33
(
7
):
1747
-
1758
.
24.
Malcovati
L
,
Karimi
M
,
Papaemmanuil
E
, et al
.
SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts
.
Blood
.
2015
;
126
(
2
):
233
-
241
.
25.
Such
E
,
Cervera
J
,
Costa
D
, et al
.
Cytogenetic risk stratification in chronic myelomonocytic leukemia
.
Haematologica
.
2011
;
96
(
3
):
375
-
383
.
26.
Greenberg
P
,
Cox
C
,
LeBeau
MM
, et al
.
International scoring system for evaluating prognosis in myelodysplastic syndromes
.
Blood
.
1997
;
89
(
6
):
2079
-
2088
.
27.
Onida
F
,
Ball
G
,
Kantarjian
HM
, et al
.
Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia
.
Cancer
.
2002
;
95
(
8
):
1673
-
1684
.
28.
Malcovati
L
,
Della Porta
MG
,
Pietra
D
, et al
.
Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis
.
Blood
.
2009
;
114
(
17
):
3538
-
3545
.
29.
DiNardo
CD
,
Daver
N
,
Jain
N
, et al
.
Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy
.
Leukemia
.
2014
;
28
(
4
):
958
-
961
.
30.
Wang
SA
,
Hasserjian
RP
,
Fox
PS
, et al
.
Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms
.
Blood
.
2014
;
123
(
17
):
2645
-
2651
.
31.
Gotlib
J
,
Maxson
JE
,
George
TI
,
Tyner
JW
.
The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment
.
Blood
.
2013
;
122
(
10
):
1707
-
1711
.
32.
Meggendorfer
M
,
Haferlach
T
,
Alpermann
T
, et al
.
Specific molecular mutation patterns delineate chronic neutrophilic leukemia, atypical chronic myeloid leukemia, and chronic myelomonocytic leukemia
.
Haematologica
.
2014
;
99
(
12
):
e244
-
e246
.
33.
Zhang
H
,
Wilmot
B
,
Bottomly
D
, et al
.
Genomic landscape of neutrophilic leukemias of ambiguous diagnosis
.
Blood
.
2019
;
134
(
11
):
867
-
879
.
34.
Makishima
H
,
Yoshizato
T
,
Yoshida
K
, et al
.
Dynamics of clonal evolution in myelodysplastic syndromes
.
Nat Genet
.
2017
;
49
(
2
):
204
-
212
.
35.
da Silva-Coelho
P
,
Kroeze
LI
,
Yoshida
K
, et al
.
Clonal evolution in myelodysplastic syndromes
.
Nat Commun
.
2017
;
8
(
1
):
15099
.
36.
Maxson
JE
,
Gotlib
J
,
Pollyea
DA
, et al
.
Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML
.
N Engl J Med
.
2013
;
368
(
19
):
1781
-
1790
.
37.
Pardanani
A
,
Lasho
TL
,
Laborde
RR
, et al
.
CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia
.
Leukemia
.
2013
;
27
(
9
):
1870
-
1873
.
38.
Worsley
A
,
Oscier
DG
,
Stevens
J
, et al
.
Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival
.
Br J Haematol
.
1988
;
68
(
1
):
17
-
21
.
39.
González-Medina
I
,
Bueno
J
,
Torrequebrada
A
,
López
A
,
Vallespí
T
,
Massagué
I
.
Two groups of chronic myelomonocytic leukaemia: myelodysplastic and myeloproliferative. Prognostic implications in a series of a single center
.
Leuk Res
.
2002
;
26
(
9
):
821
-
824
.
40.
Onida
F
,
Kantarjian
HM
,
Smith
TL
, et al
.
Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients
.
Blood
.
2002
;
99
(
3
):
840
-
849
.
41.
Such
E
,
Germing
U
,
Malcovati
L
, et al
.
Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia
.
Blood
.
2013
;
121
(
15
):
3005
-
3015
.
42.
Patnaik
MM
,
Padron
E
,
LaBorde
RR
, et al
.
Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes [published correction appears in Leukemia. 2013 Oct;27(10):2112.]
.
Leukemia
.
2013
;
27
(
7
):
1504
-
1510
.
43.
Breccia
M
,
Biondo
F
,
Latagliata
R
,
Carmosino
I
,
Mandelli
F
,
Alimena
G
.
Identification of risk factors in atypical chronic myeloid leukemia
.
Haematologica
.
2006
;
91
(
11
):
1566
-
1568
.
44.
Gambacorti-Passerini
CB
,
Donadoni
C
,
Parmiani
A
, et al
.
Recurrent ETNK1 mutations in atypical chronic myeloid leukemia
.
Blood
.
2015
;
125
(
3
):
499
-
503
.
45.
Jeromin
S
,
Haferlach
T
,
Grossmann
V
, et al
.
High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms
.
Haematologica
.
2013
;
98
(
2
):
e15
-
e17
.
46.
Broséus
J
,
Lippert
E
,
Harutyunyan
AS
, et al
.
Low rate of calreticulin mutations in refractory anaemia with ring sideroblasts and marked thrombocytosis
.
Leukemia
.
2014
;
28
(
6
):
1374
-
1376
.
47.
Broseus
J
,
Florensa
L
,
Zipperer
E
, et al
.
Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis
.
Haematologica
.
2012
;
97
(
7
):
1036
-
1041
.
48.
Patnaik
MM
,
Lasho
TL
,
Finke
CM
, et al
.
Vascular events and risk factors for thrombosis in refractory anemia with ring sideroblasts and thrombocytosis
.
Leukemia
.
2016
;
30
(
11
):
2273
-
2275
.
49.
Cannella
L
,
Breccia
M
,
Latagliata
R
,
Frustaci
A
,
Alimena
G
.
Clinical and prognostic features of patients with myelodysplastic/myeloproliferative syndrome categorized as unclassified (MDS/MPD-U) by WHO classification
.
Leuk Res
.
2008
;
32
(
3
):
514
-
516
.
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