Key Points

  • WM patients naturally segregate into 2 distinct groups using global DNA methylation patterns with memory and PC-like features.

  • WM methylation subtypes demonstrate distinct tumor-specific molecular, morphological, genetic, and phenotypic features and pathways.

Abstract

Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients.

REFERENCES

REFERENCES
1.
Dimopoulos
M
,
Kyle
R
,
Anagnostopoulos
A
,
Treon
S
.
Diagnosis and management of Waldenstrom’s macroglobulinemia
.
J Clin Oncol
.
2005
;
23
(
7
):
1564
-
1577
.
2.
Morice
W
,
Chen
D
,
Kurtin
P
,
Hanson
C
,
McPhail
E
.
Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenström’s macroglobulinemia
.
Mod Pathol
.
2009
;
22
(
6
):
807
-
816
.
3.
García-Sanz
R
,
Jiménez
C
,
Puig
N
, et al
.
Origin of Waldenstrom’s macroglobulinaemia
.
Best Pract Res Clin Haematol
.
2016
;
29
(
2
):
136
-
147
.
4.
Oakes
C
,
Seifert
M
,
Assenov
Y
, et al
.
DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia
.
Nat Genet
.
2016
;
48
(
3
):
253
-
264
.
5.
Oakes
C
,
Martin-Subero
J
.
Insight into origins, mechanisms, and utility of DNA methylation in B-cell malignancies
.
Blood
.
2018
;
132
(
10
):
999
-
1006
.
6.
Giacopelli
B
,
Zhao
Q
,
Ruppert
A
, et al
.
Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
.
Blood
.
2019
;
134
(
8
):
688
-
698
.
7.
Queiros
AC
,
Villamor
N
,
Clot
G
, et al
.
A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact
.
Leukemia
.
2015
;
29
(
3
):
598
-
605
.
8.
Queirós
A
,
Beekman
R
,
Vilarrasa-Blasi
R
, et al
.
Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage
.
Cancer Cell
.
2016
;
30
(
5
):
806
-
821
.
9.
Treon
S
,
Xu
L
,
Yang
G
, et al
.
MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia
.
N Engl J Med
.
2012
;
367
(
9
):
826
-
833
.
10.
Ngo
V
,
Young
R
,
Schmitz
R
, et al
.
Oncogenically active MYD88 mutations in human lymphoma
.
Nature
.
2011
;
470
(
7332
):
115
-
119
.
11.
Braggio
E
,
Keats
J
,
Leleu
X
, et al
.
High-resolution genomic analysis in Waldenström’s macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas
.
Clin Lymphoma Myeloma
.
2009
;
9
(
1
):
39
-
42
.
12.
Hunter
Z
,
Xu
L
,
Yang
G
, et al
.
The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis
.
Blood
.
2014
;
123
(
11
):
1637
-
1646
.
13.
Nguyen-Khac
F
,
Lambert
J
,
Chapiro
E
, et al;
Groupe d’Etude des Lymphomes de l’Adulte (GELA)
.
Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenström’s macroglobulinemia
.
Haematologica
.
2013
;
98
(
4
):
649
-
654
.
14.
Treon
S
,
Cao
Y
,
Xu
L
,
Yang
G
,
Liu
X
,
Hunter
Z
.
Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia
.
Blood
.
2014
;
123
(
18
):
2791
-
2796
.
15.
Roos-Weil
D
,
Decaudin
C
,
Armand
M
, et al
.
A recurrent activating missense mutation in Waldenström macroglobulinemia affects the DNA binding of the ETS transcription factor SPI1 and enhances proliferation
.
Cancer Discov
.
2019
;
9
(
6
):
796
-
811
.
16.
Owen
R
,
Treon
S
,
Al-Katib
A
, et al
.
Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia
.
Semin Oncol
.
2003
;
30
(
2
):
110
-
115
.
17.
Swerdlow
S
,
Campo
E
,
Harris
N
, et al
.
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
. Revised Fourth Edition.
Lyon
:
International Agency for Research on Cancer
;
2017
.
18.
Damm
F
,
Mylonas
E
,
Cosson
A
, et al
.
Acquired initiating mutations in early hematopoietic cells of CLL patients
.
Cancer Discov
.
2014
;
4
(
9
):
1088
-
1101
.
19.
Duran-Ferrer
M
,
Beekman
R
,
Martín-Subero
J
.
In silico deconvolution and purification of cancer epigenomes
.
Oncoscience
.
2017
;
4
(
3-4
):
25
-
26
.
20.
Kulis
M
,
Heath
S
,
Bibikova
M
, et al
.
Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia
.
Nat Genet
.
2012
;
44
(
11
):
1236
-
1242
.
21.
Agirre
X
,
Castellano
G
,
Pascual
M
, et al
.
Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
.
Genome Res
.
2015
;
25
(
4
):
478
-
487
.
22.
Quek
L
,
Otto
G
,
Garnett
C
, et al
.
Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage
.
J Exp Med
.
2016
;
213
(
8
):
1513
-
1535
.
23.
Blachly
J
,
Ruppert
A
,
Zhao
W
, et al
.
Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia
.
Proc Natl Acad Sci USA
.
2015
;
112
(
14
):
4322
-
4327
.
24.
Hunter
Z
,
Xu
L
,
Yang
G
, et al
.
Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia
.
Blood
.
2016
;
128
(
6
):
827
-
838
.
25.
Jourdan
M
,
Caraux
A
,
Caron
G
, et al
.
Characterization of a transitional preplasmablast population in the process of human B cell to plasma cell differentiation
.
J Immunol
.
2011
;
187
(
8
):
3931
-
3941
.
26.
Tarte
K
,
Zhan
F
,
De Vos
J
,
Klein
B
,
Shaughnessy
J
Jr.
Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation
.
Blood
.
2003
;
102
(
2
):
592
-
600
.
27.
Arribas
A
,
Rinaldi
A
,
Chiodin
G
, et al
.
Genome-wide promoter methylation of hairy cell leukemia
.
Blood Adv
.
2019
;
3
(
3
):
384
-
396
.
28.
Oakes
C
,
Claus
R
,
Gu
L
, et al
.
Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia
.
Cancer Discov
.
2014
;
4
(
3
):
348
-
361
.
29.
Kundaje
A
,
Meuleman
W
,
Ernst
J
, et al
.
Integrative analysis of 111 reference human epigenomes
.
Nature
.
2015
;
518
(
7539
):
317
-
330
. [doi].
30.
Braggio
E
,
Keats
J
,
Leleu
X
, et al
.
Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia
.
Cancer Res
.
2009
;
69
(
8
):
3579
-
3588
.
31.
Schop
R
,
Van Wier
S
,
Xu
R
, et al
.
6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance
.
Cancer Genet Cytogenet
.
2006
;
169
(
2
):
150
-
153
.
32.
Zibellini
S
,
Capello
D
,
Forconi
F
, et al
.
Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma
.
Haematologica
.
2010
;
95
(
10
):
1792
-
1796
.
33.
Gachard
N
,
Parrens
M
,
Soubeyran
I
, et al
.
IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas
.
Leukemia
.
2013
;
27
(
1
):
183
-
189
.
34.
van de Donk
N
,
Richardson
P
,
Malavasi
F
.
CD38 antibodies in multiple myeloma: back to the future
.
Blood
.
2018
;
131
(
1
):
13
-
29
.
35.
San Miguel
J
,
Vidriales
M
,
Ocio
E
, et al
.
Immunophenotypic analysis of Waldenstrom’s macroglobulinemia
.
Semin Oncol
.
2003
;
30
(
2
):
187
-
195
.
36.
Pathak
S
,
Rowczenio
DM
,
Owen
RG
, et al
.
Exploratory study of MYD88 L265P, rare NLRP3 variants, and clonal hematopoiesis
.
Arthritis Rheumatol
.
2019
;
71
(
12
):
2121
-
2125
.
37.
Genovese
G
,
Kähler
AK
,
Handsaker
RE
, et al
.
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
.
N Engl J Med
.
2014
;
371
(
26
):
2477
-
2487
.
38.
Yu
X
,
Li
W
,
Deng
Q
, et al
.
MYD88 L265P mutation in lymphoid malignancies
.
Cancer Res
.
2018
;
78
(
10
):
2457
-
2462
.
39.
de Groen
RAL
,
Schrader
AMR
,
Kersten
MJ
,
Pals
ST
,
Vermaat
JSP
.
MYD88 in the driver's seat of B-cell lymphomagenesis: from molecular mechanisms
.
Haematologica
.
2019
;
104
(
12
):
2337
-
2348
.
40.
Chng
W
,
Schop
R
,
Price-Troska
T
, et al
.
Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma
.
Blood
.
2006
;
108
(
8
):
2755
-
2763
.
41.
Gutiérrez
N
,
Ocio
E
,
de Las Rivas
J
, et al
.
Gene expression profiling of B lymphocytes and plasma cells from Waldenström’s macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals
.
Leukemia
.
2007
;
21
(
3
):
541
-
549
.
42.
Carotta
S
,
Willis
S
,
Hasbold
J
, et al
.
The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation
.
J Exp Med
.
2014
;
211
(
11
):
2169
-
2181
.
43.
López-Corral
L
,
Sarasquete
M
,
Beà
S
, et al
.
SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status
.
Leukemia
.
2012
;
26
(
12
):
2521
-
2529
.
44.
Ni
H
,
Shirazi
F
,
Baladandayuthapani
V
, et al
.
Targeting myddosome signaling in Waldenström’s macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191
.
Clin Cancer Res
.
2018
;
24
(
24
):
6408
-
6420
.
You do not currently have access to this content.