https://orcid.org/0000-0001-7419-8900
Key Points
TCL1A directly engages CDC20 in the mitotic checkpoint complex, accelerating cell cycle transit and driving genome instability in B cells.
Downregulated CDC20 in CLL cells resembles the aneuploidy phenotype and is associated with more aggressive disease and cellular features.
Subjects:
Lymphoid Neoplasia
Abstract
Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle–associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways.
Subjects:
Lymphoid Neoplasia
References
1.
Virgilio
L
, Narducci
MG
, Isobe
M
, et al. Identification of the TCL1 gene involved in T-cell malignancies
. Proc Natl Acad Sci U S A
. 1994
;91
(26
):12530
-12534
.2.
Schrader
A
, Crispatzu
G
, Oberbeck
S
, et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
. Nat Commun
. 2018
;9
(1
):697
.3.
Pekarsky
Y
, Zanesi
N
, Croce
CM
. Molecular basis of CLL
. Semin Cancer Biol
. 2010
;20
(6
):370
-376
.4.
Herling
M
, Patel
KA
, Khalili
J
, et al. TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state
. Leukemia
. 2006
;20
(2
):280
-285
.5.
Herling
M
, Patel
KA
, Teitell
MA
, et al. High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia
. Blood
. 2008
;111
(1
):328
-337
.6.
Herling
M
, Patel
KA
, Weit
N
, et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia
. Blood
. 2009
;114
(21
):4675
-4686
.7.
Hopfinger
G
, Busch
R
, Pflug
N
, et al. Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell prolymphocytic leukemia
. Cancer
. 2013
;119
(12
):2258
-2267
.8.
Ramuz
O
, Bouabdallah
R
, Devilard
E
, et al. Identification of TCL1A as an immunohistochemical marker of adverse outcome in diffuse large B-cell lymphomas
. Int J Oncol
. 2005
;26
(1
):151
-157
.9.
Herling
M
, Patel
KA
, Hsi
ED
, et al. TCL1 in B-cell tumors retains its normal b-cell pattern of regulation and is a marker of differentiation stage
. Am J Surg Pathol
. 2007
;31
(7
):1123
-1129
.10.
Aggarwal
M
, Villuendas
R
, Gomez
G
, et al. TCL1A expression delineates biological and clinical variability in B-cell lymphoma
. Mod Pathol
. 2009
;22
(2
):206
-215
.11.
Virgilio
L
, Lazzeri
C
, Bichi
R
, et al. Deregulated expression of TCL1 causes T cell leukemia in mice
. Proc Natl Acad Sci U S A
. 1998
;95
(7
):3885
-3889
.12.
Bichi
R
, Shinton
SA
, Martin
ES
, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression
. Proc Natl Acad Sci U S A
. 2002
;99
(10
):6955
-6960
.13.
Pekarsky
Y
, Koval
A
, Hallas
C
, et al. Tcl1 enhances Akt kinase activity and mediates its nuclear translocation
. Proc Natl Acad Sci U S A
. 2000
;97
(7
):3028
-3033
.14.
Laine
J
, Künstle
G
, Obata
T
, Sha
M
, Noguchi
M
. The protooncogene TCL1 is an Akt kinase coactivator
. Mol Cell
. 2000
;6
(2
):395
-407
.15.
Pekarsky
Y
, Palamarchuk
A
, Maximov
V
, et al. Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL
. Proc Natl Acad Sci U S A
. 2008
;105
(50
):19643
-19648
.16.
Oberbeck
S
, Schrader
A
, Warner
K
, et al. Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling
. Blood
. 2020
;136
(24
):2786
-2802
.17.
Kharas
MG
, Okabe
R
, Ganis
JJ
, et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice
. Blood
. 2010
;115
(7
):1406
-1415
.18.
Stachelscheid
J
, Jiang
Q
, Herling
M
. The modes of dysregulation of the proto-oncogene T-cell leukemia/lymphoma 1A
. Cancers (Basel)
. 2021
;13
(21
):5455
.19.
Klein
U
, Lia
M
, Crespo
M
, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia
. Cancer Cell
. 2010
;17
(1
):28
-40
.20.
Kienle
DL
, Korz
C
, Hosch
B
, et al. Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes
. J Clin Oncol
. 2005
;23
(16
):3780
-3792
.21.
Decker
T
, Schneller
F
, Hipp
S
, et al. Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27
. Leukemia
. 2002
;16
(3
):327
-334
.22.
Schmidt
M
, Rohe
A
, Platzer
C
, et al. Regulation of G2/M transition by inhibition of WEE1 and PKMYT1 kinases
. Molecules
. 2017
;22
(12
):2045
.23.
Chao
WCH
, Kulkarni
K
, Zhang
Z
, Kong
EH
, Barford
D
. Structure of the mitotic checkpoint complex
. Nature
. 2012
;484
(7393
):208
-213
.24.
Vleugel
M
, Hoogendoorn
E
, Snel
B
, Kops
GJPL
. Evolution and function of the mitotic checkpoint
. Dev Cell
. 2012
;23
(2
):239
-250
.25.
Fedorchenko
O
, Stiefelhagen
M
, Peer-Zada
AA
, et al. CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia
. Blood
. 2013
;121
(20
):4126
-4136
.26.
Newrzela
S
, Cornils
K
, Li
Z
, et al. Resistance of mature T cells to oncogene transformation
. Blood
. 2008
;112
(6
):2278
-2286
.27.
Hallek
M
, Fischer
K
, Fingerle-Rowson
G
, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial
. Lancet
. 2010
;376
(9747
):1164
-1174
.28.
Vasyutina
E
, Boucas
JM
, Bloehdorn
J
, et al. The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL
. Leukemia
. 2015
;29
(10
):2003
-2014
.29.
Bloehdorn
J
, Braun
A
, Taylor-Weiner
A
, et al. Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
. Nat Commun
. 2021
;12
(1
):5395
.30.
Kohlhaas
V
, Blakemore
SJ
, Al-Maarri
M
, et al. Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
. Blood
. 2021
;137
(5
):646
-660
.31.
Perez-Riverol
Y
, Csordas
A
, Bai
J
, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data
. Nucleic Acids Res
. 2019
;47
(D1
):D442
-D450
.32.
Sancar
A
, Lindsey-Boltz
LA
, Unsal-Kaçmaz
K
, Linn
S
. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints
. Annu Rev Biochem
. 2004
;73
(1
):39
-85
.33.
Bailis
JM
, Forsburg
SL
. MCM proteins: DNA damage, mutagenesis and repair
. Curr Opin Genet Dev
. 2004
;14
(1
):17
-21
.34.
Kaneta
Y
, Ullrich
A
. NEK9 depletion induces catastrophic mitosis by impairment of mitotic checkpoint control and spindle dynamics
. Biochem Biophys Res Commun
. 2013
;442
(3-4
):139
-146
.35.
Lara-Gonzalez
P
, Moyle
MW
, Budrewicz
J
, et al. The G2-to-M transition is ensured by a dual mechanism that protects cyclin B from degradation by Cdc20-activated APC/C
. Dev Cell
. 2019
;51
(3
):313
-325.e10
.36.
de Vries
SJ
, Bonvin
AMJJ
. CPORT: a consensus interface predictor and its performance in prediction-driven docking with HADDOCK
. PLoS One
. 2011
;6
(3
):e17695
.37.
Dominguez
C
, Boelens
R
, Bonvin
AMJJ
. HADDOCK: a protein-protein docking approach based on biochemical or biophysical information
. J Am Chem Soc
. 2003
;125
(7
):1731
-1737
.38.
Michnick
SW
, Ear
PH
, Landry
C
, Malleshaiah
MK
, Messier
V
. Protein-fragment complementation assays for large-scale analysis, functional dissection and dynamic studies of protein-protein interactions in living cells
. Methods Mol Biol
. 2011
;756
:395
-425
.39.
Pfleger
CM
, Lee
E
, Kirschner
MW
. Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex
. Genes Dev
. 2001
;15
(18
):2396
-2407
.40.
Labit
H
, Fujimitsu
K
, Bayin
NS
, et al. Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C
. EMBO J
. 2012
;31
(15
):3351
-3362
.41.
Ge
S
, Skaar
JR
, Pagano
M
. APC/C- and Mad2-mediated degradation of Cdc20 during spindle checkpoint activation
. Cell Cycle
. 2009
;8
(1
):167
-171
.42.
Auguin
D
, Barthe
P
, Royer
C
, et al. Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins
. J Biol Chem
. 2004
;279
(34
):35890
-35902
.43.
Dosztányi
Z
, Csizmok
V
, Tompa
P
, Simon
I
. IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content
. Bioinformatics
. 2005
;21
(16
):3433
-3434
.44.
Izawa
D
, Pines
J
. Mad2 and the APC/C compete for the same site on Cdc20 to ensure proper chromosome segregation
. J Cell Biol
. 2012
;199
(1
):27
-37
.45.
Jia
L
, Li
B
, Yu
H
. The Bub1–Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation
. Nat Commun
. 2016
;7
(1
):10818
.46.
Landau
DA
, Carter
SL
, Stojanov
P
, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia
. Cell
. 2013
;152
(4
):714
-726
.47.
Landau
DA
, Tausch
E
, Taylor-Weiner
AN
, et al. Mutations driving CLL and their evolution in progression and relapse
. Nature
. 2015
;526
(7574
):525
-530
.48.
Quesada
V
, Conde
L
, Villamor
N
, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia
. Nat Genet
. 2011
;44
(1
):47
-52
.49.
Puente
XS
, Beà
S
, Valdés-Mas
R
, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia
. Nature
. 2015
;526
(7574
):519
-524
.50.
Haferlach
T
, Kohlmann
A
, Wieczorek
L
, et al. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group
. J Clin Oncol
. 2010
;28
(15
):2529
-2537
.51.
Suljagic
M
, Longo
PG
, Bennardo
S
, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling
. Blood
. 2010
;116
(23
):4894
-4905
.52.
Gaudio
E
, Spizzo
R
, Paduano
F
, et al. Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies
. Blood
. 2012
;119
(1
):180
-187
.53.
Sivina
M
, Hartmann
E
, Vasyutina
E
, et al. Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia
. Leukemia
. 2012
;26
(8
):1812
-1820
.54.
Barlow
C
, Hirotsune
S
, Paylor
R
, et al. Atm-deficient mice: a paradigm of ataxia telangiectasia
. Cell
. 1996
;86
(1
):159
-171
.55.
Lanemo Myhrinder
A
, Hellqvist
E
, Bergh
A-C
, et al. Molecular characterization of neoplastic and normal “sister” lymphoblastoid B-cell lines from chronic lymphocytic leukemia
. Leuk Lymphoma
. 2013
;54
(8
):1769
-1779
.56.
Yamaguchi
M
, VanderLinden
R
, Weissmann
F
, et al. Cryo-EM of mitotic checkpoint complex-bound APC/C reveals reciprocal and conformational regulation of ubiquitin ligation
. Mol Cell
. 2016
;63
(4
):593
-607
.57.
Wang
S
, Chen
B
, Zhu
Z
, et al. CDC20 overexpression leads to poor prognosis in solid tumors: a system review and meta-analysis
. Medicine (Baltimore)
. 2018
;97
(52
):e13832
.58.
Alfarsi
LH
, Ansari
R El
, Craze
ML
, et al. CDC20 expression in oestrogen receptor positive breast cancer predicts poor prognosis and lack of response to endocrine therapy
. Breast Cancer Res Treat
. 2019
;178
(3
):535
-544
.59.
Song
C
, Lowe
VJ
, Lee
S
. Inhibition of Cdc20 suppresses the metastasis in triple negative breast cancer (TNBC)
. Breast Cancer
. 2021
;28
(5
):1073
-1086
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