Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman’s rank correlation coefficient. Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (−1,132 to −996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.

1.
Bray
F
,
Ferlay
J
,
Soerjomataram
I
,
Siegel
RL
,
Torre
LA
,
Jemal
A
.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
.
CA Cancer J Clin
.
2018 Nov
;
68
(
6
):
394
424
. .
2.
Alizadeh
AA
,
Eisen
MB
,
Davis
RE
,
Ma
C
,
Lossos
IS
,
Rosenwald
A
,
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
.
Nature
.
2000 Feb 3
;
403
(
6769
):
503
11
. .
3.
Salles
G
,
Barrett
M
,
Foà
R
,
Maurer
J
,
O'Brien
S
,
Valente
N
,
Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience
.
Adv Ther
.
2017 Oct
;
34
(
10
):
2232
73
. .
4.
Guo
L
,
Lin
P
,
Xiong
H
,
Tu
S
,
Chen
G
.
Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment
.
Biochim Biophys Acta Rev Cancer
.
2018 Apr
;
1869
(
2
):
85
96
. .
5.
Crump
M
,
Neelapu
SS
,
Farooq
U
,
Van Den Neste
E
,
Kuruvilla
J
,
Westin
J
,
Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study
.
Blood
.
2017 Oct 19
;
130
(
16
):
1800
8
. .
6.
Bouwstra
R
,
He
Y
,
de Boer
J
,
Kooistra
H
,
Cendrowicz
E
,
Fehrmann
RSN
,
CD47 expression defines efficacy of rituximab with CHOP in non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma patients (DLBCL), but not in GCB DLBCL
.
Cancer Immunol Res
.
2019 Oct
;
7
(
10
):
1663
71
. .
7.
Cho
MC
,
Chung
Y
,
Jang
S
,
Park
CJ
,
Chi
HS
,
Huh
J
,
Prognostic impact of germinal center B-cell-like and non-germinal center B-cell-like subtypes of bone marrow involvement in patients with diffuse large B-cell lymphoma treated with R-CHOP
.
Medicine
.
2018 Nov
;
97
(
45
):
e13046
. .
8.
Jin
X
,
Shi
Q
,
Li
Q
,
Zhou
L
,
Wang
J
,
Jiang
L
,
CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-κB signaling
.
Leukemia
.
2020 May
;
34
(
5
):
1305
14
. .
9.
Zhu
F
,
Guo
H
,
Bates
PD
,
Zhang
S
,
Zhang
H
,
Nomie
KJ
,
PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells
.
Leukemia
.
2019 Dec
;
33
(
12
):
2898
911
. .
10.
Kim
HG
,
Hien
TT
,
Han
EH
,
Hwang
YP
,
Choi
JH
,
Kang
KW
,
Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation
.
Br J Pharmacol
.
2011 Mar
;
162
(
5
):
1096
108
. .
11.
Morgan
MA
,
Magnusdottir
E
,
Kuo
TC
,
Tunyaplin
C
,
Harper
J
,
Arnold
SJ
,
Blimp-1/Prdm1 alternative promoter usage during mouse development and plasma cell differentiation
.
Mol Cell Biol
.
2009 Nov
;
29
(
21
):
5813
27
. .
12.
Wang
YH
,
Tsai
DY
,
Ko
YA
,
Yang
TT
,
Lin
IY
,
Hung
KH
,
Blimp-1 contributes to the development and function of regulatory B cells
.
Front Immunol
.
2019
;
10
:
1909
.
13.
Śledzińska
A
,
Vila de Mucha
M
,
Bergerhoff
K
,
Hotblack
A
,
Demane
DF
,
Ghorani
E
,
Regulatory T cells restrain interleukin-2- and blimp-1-dependent acquisition of cytotoxic function by CD4(+) T cells
.
Immunity
.
2020 Jan 14
;
52
(
1
):
151
66.e6
.
14.
Chang
DH
,
Angelin-Duclos
C
,
Calame
K
.
BLIMP-1: trigger for differentiation of myeloid lineage
.
Nat Immunol
.
2000 Aug
;
1
(
2
):
169
76
. .
15.
Kim
SJ
.
Immunological function of Blimp-1 in dendritic cells and relevance to autoimmune diseases
.
Immunol Res
.
2015 Dec
;
63
(
1–3
):
113
20
. .
16.
Elias
S
,
Robertson
EJ
,
Bikoff
EK
,
Mould
AW
.
Blimp-1/PRDM1 is a critical regulator of type III interferon responses in mammary epithelial cells
.
Sci Rep
.
2018 Jan 10
;
8
(
1
):
237
. .
17.
Boi
M
,
Zucca
E
,
Inghirami
G
,
Bertoni
F
.
PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas
.
Leuk Lymphoma
.
2015 May
;
56
(
5
):
1223
8
. .
18.
Xia
Y
,
Xu-Monette
ZY
,
Tzankov
A
,
Li
X
,
Manyam
GC
,
Murty
V
,
Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma
.
Leukemia
.
2017 Mar
;
31
(
3
):
625
36
. .
19.
Ting
CY
,
Gan
GG
,
Bee-Lan Ong
D
,
Tan
SY
,
Bee
PC
.
Extranodal site of diffuse large B-cell lymphoma and the risk of R-CHOP chemotherapy resistance and early relapse
.
Int J Clin Pract
.
2020 Oct
;
74
(
10
):
e13594
. .
20.
Abdulla
M
,
Hollander
P
,
Pandzic
T
,
Mansouri
L
,
Ednersson
SB
,
Andersson
PO
,
Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma
.
Am J Hematol
.
2020 Jan
;
95
(
1
):
57
67
. .
21.
Kuo
TC
,
Calame
KL
.
B lymphocyte-induced maturation protein (Blimp)-1, IFN regulatory factor (IRF)-1, and IRF-2 can bind to the same regulatory sites
.
J Immunol
.
2004 Nov 1
;
173
(
9
):
5556
63
. .
22.
Maxwell
SA
,
Cherry
EM
,
Bayless
KJ
.
Akt, 14-3-3ζ, and vimentin mediate a drug-resistant invasive phenotype in diffuse large B-cell lymphoma
.
Leuk Lymphoma
.
2011 May
;
52
(
5
):
849
64
. .
23.
Hitz
F
,
Connors
JM
,
Gascoyne
RD
,
Hoskins
P
,
Moccia
A
,
Savage
KJ
,
Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment
.
Ann Hematol
.
2015 Nov
;
94
(
11
):
1839
43
. .
24.
He
XH
,
Li
B
,
Yang
S
,
Lu
N
,
Zhang
X
,
Zou
SM
,
R-CHOP regimen can significantly decrease the risk of disease relapse and progression in patients with non-germinal center B-cell subtype diffuse large B-cell lymphoma
.
Chin J Cancer
.
2012 Jun
;
31
(
6
):
306
14
. .
25.
Thieblemont
C
,
Briere
J
,
Mounier
N
,
Voelker
HU
,
Cuccuini
W
,
Hirchaud
E
,
The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study
.
J Clin Oncol
.
2011 Nov 1
;
29
(
31
):
4079
87
. .
26.
Ni
Y
,
Yin
G
,
Xiao
Z
,
Fan
L
,
Wang
L
,
Wu
Y
,
MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients
.
Tumour Biol
.
2016
;
37
(
1
):
1237
44
.
27.
Hu
LL
,
Yu
B
,
Yang
J
.
MDR1 polymorphisms associated with risk and survival in diffuse large B-cell lymphoma
.
Leuk Lymphoma
.
2013 Jun
;
54
(
6
):
1188
93
. .
28.
Wang
Z
,
Zhang
L
,
Ni
Z
,
Sun
J
,
Gao
H
,
Cheng
Z
,
Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity
.
Tumour Biol
.
2015 Dec
;
36
(
12
):
9499
510
. .
29.
Zhao
P
,
Wang
S
,
Jiang
J
,
Liu
H
,
Zhu
X
,
Zhao
N
,
TIPE2 sensitizes osteosarcoma cells to cis-platin by down-regulating MDR1 via the TAK1- NF-κB and - AP-1 pathways
.
Mol Immunol
.
2018
;
101
(
101
):
471
8
. .
30.
Jin
Z
,
Qing
K
,
Ouyang
Y
,
Liu
Z
,
Wang
W
,
Li
X
,
Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma
.
J Exp Clin Cancer Res
.
2016 Mar 24
;
35
:
52
. .
31.
Wilson
WH
,
Young
RM
,
Schmitz
R
,
Yang
Y
,
Pittaluga
S
,
Wright
G
,
Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma
.
Nat Med
.
2015 Aug
;
21
(
8
):
922
6
. .
32.
Furtado
M
,
Johnson
R
,
Kruger
A
,
Turner
D
,
Rule
S
.
Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma
.
Br J Haematol
.
2015 Jan
;
168
(
1
):
55
62
. .
33.
Xian
M
,
Cao
H
,
Cao
J
,
Shao
X
,
Zhu
D
,
Zhang
N
,
Bortezomib sensitizes human osteosarcoma cells to adriamycin-induced apoptosis through ROS-dependent activation of p-eIF2α/ATF4/CHOP axis
.
Int J Cancer
.
2017
;
141
(
5
):
1029
41
. .
34.
Savage
KJ
,
Slack
GW
,
Mottok
A
,
Sehn
LH
,
Villa
D
,
Kansara
R
,
Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL
.
Blood
.
2016 May 5
;
127
(
18
):
2182
8
. .
35.
Liu
YY
,
Leboeuf
C
,
Shi
JY
,
Li
JM
,
Wang
L
,
Shen
Y
,
Rituximab plus CHOP (R-CHOP) overcomes PRDM1-associated resistance to chemotherapy in patients with diffuse large B-cell lymphoma
.
Blood
.
2007 Jul 1
;
110
(
1
):
339
44
. .
36.
Mandelbaum
J
,
Bhagat
G
,
Tang
H
,
Mo
T
,
Brahmachary
M
,
Shen
Q
,
BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma
.
Cancer Cell
.
2010 Dec 14
;
18
(
6
):
568
79
. .
37.
Turturro
F
.
Constitutive NF- κB activation underlines major mechanism of drug resistance in relapsed refractory diffuse large B cell lymphoma
.
Biomed Res Int
.
2015
;
2015
:
484537
. .
38.
Zhao
WL
,
Liu
YY
,
Zhang
QL
,
Wang
L
,
Leboeuf
C
,
Zhang
YW
,
PRDM1 is involved in chemoresistance of T-cell lymphoma and down-regulated by the proteasome inhibitor
.
Blood
.
2008 Apr
;
111
(
7
):
3867
71
. .
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