Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway

Sampath Ramachandiran, Arsene Adon, Xiangxue Guo, Yi Wang, Huichen Wang, Zhengjia Chen, Jeanne Kowalski, Ustun R. Sunay, Andrew N. Young, Theresa Brown, Jessica C. Mar, Yuhong Du, Haian Fu, Karen P. Mann, Yasodha Natkunam, Lawrence H. Boise, Harold I. Saavedra, Izidore S. Lossos, Leon Bernal-Mizrachi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.

Original languageEnglish (US)
Pages (from-to)2341-2351
Number of pages11
JournalInternational Journal of Cancer
Volume136
Issue number10
DOIs
StatePublished - May 15 2015

Fingerprint

Chromosomal Instability
Lymphoma, Large B-Cell, Diffuse
Centrosome
DNA Damage
Cyclin G2
NF-kappa B
Lymphoma
B-Lymphocytes
Anaphase
Germinal Center
Genomic Instability
Genetic Promoter Regions
DNA Repair
Chromosomes
Genome

Keywords

  • chromosome stability
  • diffuse large cell lymphoma
  • NF-κB

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ramachandiran, S., Adon, A., Guo, X., Wang, Y., Wang, H., Chen, Z., ... Bernal-Mizrachi, L. (2015). Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway. International Journal of Cancer, 136(10), 2341-2351. https://doi.org/10.1002/ijc.29301

Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway. / Ramachandiran, Sampath; Adon, Arsene; Guo, Xiangxue; Wang, Yi; Wang, Huichen; Chen, Zhengjia; Kowalski, Jeanne; Sunay, Ustun R.; Young, Andrew N.; Brown, Theresa; Mar, Jessica C.; Du, Yuhong; Fu, Haian; Mann, Karen P.; Natkunam, Yasodha; Boise, Lawrence H.; Saavedra, Harold I.; Lossos, Izidore S.; Bernal-Mizrachi, Leon.

In: International Journal of Cancer, Vol. 136, No. 10, 15.05.2015, p. 2341-2351.

Research output: Contribution to journalArticle

Ramachandiran, S, Adon, A, Guo, X, Wang, Y, Wang, H, Chen, Z, Kowalski, J, Sunay, UR, Young, AN, Brown, T, Mar, JC, Du, Y, Fu, H, Mann, KP, Natkunam, Y, Boise, LH, Saavedra, HI, Lossos, IS & Bernal-Mizrachi, L 2015, 'Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway', International Journal of Cancer, vol. 136, no. 10, pp. 2341-2351. https://doi.org/10.1002/ijc.29301
Ramachandiran, Sampath ; Adon, Arsene ; Guo, Xiangxue ; Wang, Yi ; Wang, Huichen ; Chen, Zhengjia ; Kowalski, Jeanne ; Sunay, Ustun R. ; Young, Andrew N. ; Brown, Theresa ; Mar, Jessica C. ; Du, Yuhong ; Fu, Haian ; Mann, Karen P. ; Natkunam, Yasodha ; Boise, Lawrence H. ; Saavedra, Harold I. ; Lossos, Izidore S. ; Bernal-Mizrachi, Leon. / Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway. In: International Journal of Cancer. 2015 ; Vol. 136, No. 10. pp. 2341-2351.
@article{30d8f5db35ed49e8939f3ecb3cb56eaf,
title = "Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway",
abstract = "Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.",
keywords = "chromosome stability, diffuse large cell lymphoma, NF-κB",
author = "Sampath Ramachandiran and Arsene Adon and Xiangxue Guo and Yi Wang and Huichen Wang and Zhengjia Chen and Jeanne Kowalski and Sunay, {Ustun R.} and Young, {Andrew N.} and Theresa Brown and Mar, {Jessica C.} and Yuhong Du and Haian Fu and Mann, {Karen P.} and Yasodha Natkunam and Boise, {Lawrence H.} and Saavedra, {Harold I.} and Lossos, {Izidore S.} and Leon Bernal-Mizrachi",
year = "2015",
month = "5",
day = "15",
doi = "10.1002/ijc.29301",
language = "English (US)",
volume = "136",
pages = "2341--2351",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Chromosome instability in diffuse large B cell lymphomas is suppressed by activation of the noncanonical NF-κB pathway

AU - Ramachandiran, Sampath

AU - Adon, Arsene

AU - Guo, Xiangxue

AU - Wang, Yi

AU - Wang, Huichen

AU - Chen, Zhengjia

AU - Kowalski, Jeanne

AU - Sunay, Ustun R.

AU - Young, Andrew N.

AU - Brown, Theresa

AU - Mar, Jessica C.

AU - Du, Yuhong

AU - Fu, Haian

AU - Mann, Karen P.

AU - Natkunam, Yasodha

AU - Boise, Lawrence H.

AU - Saavedra, Harold I.

AU - Lossos, Izidore S.

AU - Bernal-Mizrachi, Leon

PY - 2015/5/15

Y1 - 2015/5/15

N2 - Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.

AB - Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.

KW - chromosome stability

KW - diffuse large cell lymphoma

KW - NF-κB

UR - http://www.scopus.com/inward/record.url?scp=84924308669&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924308669&partnerID=8YFLogxK

U2 - 10.1002/ijc.29301

DO - 10.1002/ijc.29301

M3 - Article

C2 - 25359525

AN - SCOPUS:84924308669

VL - 136

SP - 2341

EP - 2351

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 10

ER -