The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

Anke Maes; Ken Maes; Hendrik De Raeve; Eva De Smedt; Philip Vlummens; Vanessa Szablewski; Julie Devin; Sylvia Faict; Kim De Veirman; Eline Menu; Fritz Offner; Marcel Spaargaren; Jérôme Moreaux; Karin Vanderkerken; Els Van Valckenborgh; Elke De Bruyne

doi:10.1038/s41416-019-0471-0

The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

Anke Maes, Ken Maes, Hendrik De Raeve, Eva De Smedt, Philip Vlummens, Vanessa Szablewski, Julie Devin, Sylvia Faict, Kim De Veirman, Eline Menu, Fritz Offner, Marcel Spaargaren, Jérôme Moreaux, Karin Vanderkerken, Els Van Valckenborgh, Elke De Bruyne

Research output: Contribution to journal › Article

9 Citations (Scopus)

Abstract

BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL.

METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot.

RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax.

CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL.

Original language	English
Pages (from-to)	1137-1146
Number of pages	10
Journal	British Journal of Cancer
Volume	120
Issue number	12
DOIs	https://doi.org/10.1038/s41416-019-0471-0
Publication status	Published - 11 Jun 2019

Keywords

large B-cell lymphoma
aggressive B-cell non-Hodgkin lymphomas
DLBCL

Access to Document

10.1038/s41416-019-0471-0

Link to publication in Scopus

1 Active

SRP48: Strategic Research Programme: Cancer Cell Targeting in Myeloma and Melanoma (MyMe)
Thielemans, K., Vanderkerken, K. & Breckpot, K.
1/11/17 → 31/10/22
Project: Fundamental

Cite this

Maes, Anke ; Maes, Ken ; De Raeve, Hendrik ; De Smedt, Eva ; Vlummens, Philip ; Szablewski, Vanessa ; Devin, Julie ; Faict, Sylvia ; De Veirman, Kim ; Menu, Eline ; Offner, Fritz ; Spaargaren, Marcel ; Moreaux, Jérôme ; Vanderkerken, Karin ; Van Valckenborgh, Els ; De Bruyne, Elke. / The anaphase-promoting complex/cyclosome : a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma. In: British Journal of Cancer. 2019 ; Vol. 120, No. 12. pp. 1137-1146.

@article{c766db3393b548f28fe858213f76d56d,

title = "The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma",

abstract = "BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL.METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot.RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax.CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL.",

keywords = "large B-cell lymphoma, aggressive B-cell non-Hodgkin lymphomas, DLBCL",

author = "Anke Maes and Ken Maes and {De Raeve}, Hendrik and {De Smedt}, Eva and Philip Vlummens and Vanessa Szablewski and Julie Devin and Sylvia Faict and {De Veirman}, Kim and Eline Menu and Fritz Offner and Marcel Spaargaren and J{\'e}r{\^o}me Moreaux and Karin Vanderkerken and {Van Valckenborgh}, Els and {De Bruyne}, Elke",

year = "2019",

month = "6",

day = "11",

doi = "10.1038/s41416-019-0471-0",

language = "English",

volume = "120",

pages = "1137--1146",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "12",

}

Maes, A , Maes, K , De Raeve, H , De Smedt, E , Vlummens, P, Szablewski, V, Devin, J, Faict, S , De Veirman, K , Menu, E, Offner, F, Spaargaren, M, Moreaux, J, Vanderkerken, K, Van Valckenborgh, E & De Bruyne, E 2019, 'The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma', British Journal of Cancer, vol. 120, no. 12, pp. 1137-1146. https://doi.org/10.1038/s41416-019-0471-0

The anaphase-promoting complex/cyclosome : a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma. / Maes, Anke ; Maes, Ken ; De Raeve, Hendrik ; De Smedt, Eva ; Vlummens, Philip; Szablewski, Vanessa; Devin, Julie; Faict, Sylvia ; De Veirman, Kim ; Menu, Eline; Offner, Fritz; Spaargaren, Marcel; Moreaux, Jérôme; Vanderkerken, Karin; Van Valckenborgh, Els; De Bruyne, Elke.

In: British Journal of Cancer, Vol. 120, No. 12, 11.06.2019, p. 1137-1146.

Research output: Contribution to journal › Article

TY - JOUR

T1 - The anaphase-promoting complex/cyclosome

T2 - a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

AU - Maes, Anke

AU - Maes, Ken

AU - De Raeve, Hendrik

AU - De Smedt, Eva

AU - Vlummens, Philip

AU - Szablewski, Vanessa

AU - Devin, Julie

AU - Faict, Sylvia

AU - De Veirman, Kim

AU - Menu, Eline

AU - Offner, Fritz

AU - Spaargaren, Marcel

AU - Moreaux, Jérôme

AU - Vanderkerken, Karin

AU - Van Valckenborgh, Els

AU - De Bruyne, Elke

PY - 2019/6/11

Y1 - 2019/6/11

N2 - BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL.METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot.RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax.CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL.

AB - BACKGROUND: The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL.METHODS: The expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot.RESULTS: We demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax.CONCLUSION: We identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL.

KW - large B-cell lymphoma

KW - aggressive B-cell non-Hodgkin lymphomas

KW - DLBCL

UR - http://www.scopus.com/inward/record.url?scp=85065915375&partnerID=8YFLogxK

U2 - 10.1038/s41416-019-0471-0

DO - 10.1038/s41416-019-0471-0

M3 - Article

C2 - 31089208

VL - 120

SP - 1137

EP - 1146

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 12

ER -

The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

Abstract

Keywords

Access to Document

Fingerprint

Projects

SRP48: Strategic Research Programme: Cancer Cell Targeting in Myeloma and Melanoma (MyMe)

Cite this