Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Christina M. Annunziata; R. Eric Davis; Yulia Demchenko; William Bellamy; Ana Gabrea; Fenghuang Zhan; Georg Lenz; Ichiro Hanamura; George Wright; Wenming Xiao; Sandeep Dave; Elaine M. Hurt; Bruce Tan; Hong Zhao; Owen Stephens; Madhumita Santra; David R. Williams; Lenny Dang; Bart Barlogie; John D. Shaughnessy; W. Michael Kuehl; Louis M. Staudt

doi:10.1016/j.ccr.2007.07.004

Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Christina M. Annunziata, R. Eric Davis, Yulia Demchenko, William Bellamy, Ana Gabrea, Fenghuang Zhan, Georg Lenz, Ichiro Hanamura, George Wright, Wenming Xiao, Sandeep Dave, Elaine M. Hurt, Bruce Tan, Hong Zhao, Owen Stephens, Madhumita Santra, David R. Williams, Lenny Dang, Bart Barlogie, John D. ShaughnessyW. Michael Kuehl, Louis M. Staudt

Research output: Contribution to journal › Article › peer-review

839 Scopus citations

Abstract

Mechanisms of constitutive NF-κB signaling in multiple myeloma are unknown. An inhibitor of IκB kinase β (IKKβ) targeting the classical NF-κB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-κB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-κB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-κB pathway is frequent in myeloma and suggest that IKKβ inhibitors hold promise for the treatment of this disease.

Original language	English (US)
Pages (from-to)	115-130
Number of pages	16
Journal	Cancer cell
Volume	12
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2007.07.004
State	Published - Aug 14 2007
Externally published	Yes

Keywords

CELLCYCLE
SIGNALING

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccr.2007.07.004

Cite this

Annunziata, C. M., Davis, R. E., Demchenko, Y., Bellamy, W., Gabrea, A., Zhan, F., Lenz, G., Hanamura, I., Wright, G., Xiao, W., Dave, S., Hurt, E. M., Tan, B., Zhao, H., Stephens, O., Santra, M., Williams, D. R., Dang, L., Barlogie, B., ... Staudt, L. M. (2007). Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma. Cancer cell, 12(2), 115-130. https://doi.org/10.1016/j.ccr.2007.07.004

Annunziata, CM, Davis, RE, Demchenko, Y, Bellamy, W, Gabrea, A, Zhan, F, Lenz, G, Hanamura, I, Wright, G, Xiao, W, Dave, S, Hurt, EM, Tan, B, Zhao, H, Stephens, O, Santra, M, Williams, DR, Dang, L, Barlogie, B, Shaughnessy, JD, Kuehl, WM & Staudt, LM 2007, 'Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma', Cancer cell, vol. 12, no. 2, pp. 115-130. https://doi.org/10.1016/j.ccr.2007.07.004

@article{d0660b30dc5a4591a813ed56340948af,

title = "Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma",

abstract = "Mechanisms of constitutive NF-κB signaling in multiple myeloma are unknown. An inhibitor of IκB kinase β (IKKβ) targeting the classical NF-κB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-κB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-κB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-κB pathway is frequent in myeloma and suggest that IKKβ inhibitors hold promise for the treatment of this disease.",

keywords = "CELLCYCLE, SIGNALING",

author = "Annunziata, {Christina M.} and Davis, {R. Eric} and Yulia Demchenko and William Bellamy and Ana Gabrea and Fenghuang Zhan and Georg Lenz and Ichiro Hanamura and George Wright and Wenming Xiao and Sandeep Dave and Hurt, {Elaine M.} and Bruce Tan and Hong Zhao and Owen Stephens and Madhumita Santra and Williams, {David R.} and Lenny Dang and Bart Barlogie and Shaughnessy, {John D.} and Kuehl, {W. Michael} and Staudt, {Louis M.}",

note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (L.M.S., W.M.K.); NIH grant CA55819 (B.B. and J.D.S.); and the Lebow Fund for the Cure (J.D.S.). L.D. is an employee of Millennium Pharmaceuticals, Inc., Cambridge, MA. The authors would like to acknowledge the technical contributions of Leslie Brents. W.M.K. thanks Leif Bergsagel for suggesting the possibility of a NIK translocation in JJN3 cells. ",

year = "2007",

month = aug,

day = "14",

doi = "10.1016/j.ccr.2007.07.004",

language = "English (US)",

volume = "12",

pages = "115--130",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

AU - Annunziata, Christina M.

AU - Davis, R. Eric

AU - Demchenko, Yulia

AU - Bellamy, William

AU - Gabrea, Ana

AU - Zhan, Fenghuang

AU - Lenz, Georg

AU - Hanamura, Ichiro

AU - Wright, George

AU - Xiao, Wenming

AU - Dave, Sandeep

AU - Hurt, Elaine M.

AU - Tan, Bruce

AU - Zhao, Hong

AU - Stephens, Owen

AU - Santra, Madhumita

AU - Williams, David R.

AU - Dang, Lenny

AU - Barlogie, Bart

AU - Shaughnessy, John D.

AU - Kuehl, W. Michael

AU - Staudt, Louis M.

N1 - Funding Information: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (L.M.S., W.M.K.); NIH grant CA55819 (B.B. and J.D.S.); and the Lebow Fund for the Cure (J.D.S.). L.D. is an employee of Millennium Pharmaceuticals, Inc., Cambridge, MA. The authors would like to acknowledge the technical contributions of Leslie Brents. W.M.K. thanks Leif Bergsagel for suggesting the possibility of a NIK translocation in JJN3 cells.

PY - 2007/8/14

Y1 - 2007/8/14

N2 - Mechanisms of constitutive NF-κB signaling in multiple myeloma are unknown. An inhibitor of IκB kinase β (IKKβ) targeting the classical NF-κB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-κB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-κB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-κB pathway is frequent in myeloma and suggest that IKKβ inhibitors hold promise for the treatment of this disease.

AB - Mechanisms of constitutive NF-κB signaling in multiple myeloma are unknown. An inhibitor of IκB kinase β (IKKβ) targeting the classical NF-κB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-κB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-κB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-κB pathway is frequent in myeloma and suggest that IKKβ inhibitors hold promise for the treatment of this disease.

KW - CELLCYCLE

KW - SIGNALING

UR - http://www.scopus.com/inward/record.url?scp=34547562418&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547562418&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2007.07.004

DO - 10.1016/j.ccr.2007.07.004

M3 - Article

C2 - 17692804

AN - SCOPUS:34547562418

SN - 1535-6108

VL - 12

SP - 115

EP - 130

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this