Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

Jonathan J. Keats; Rafael Fonseca; Marta Chesi; Roelandt Schop; Angela Baker; Wee Joo Chng; Scott Van Wier; Rodger Tiedemann; Chang Xin Shi; Michael Sebag; Esteban Braggio; Travis Henry; Yuan Xiao Zhu; Homer Fogle; Tammy Price-Troska; Gregory Ahmann; Catherine Mancini; Leslie A. Brents; Shaji Kumar; Philip Greipp; Angela Dispenzieri; Barb Bryant; George Mulligan; Laurakay Bruhn; Michael Barrett; Riccardo Valdez; Jeff Trent; A. Keith Stewart; John Carpten; P. Leif Bergsagel

doi:10.1016/j.ccr.2007.07.003

Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

Jonathan J. Keats, Rafael Fonseca, Marta Chesi, Roelandt Schop, Angela Baker, Wee Joo Chng, Scott Van Wier, Rodger Tiedemann, Chang Xin Shi, Michael Sebag, Esteban Braggio, Travis Henry, Yuan Xiao Zhu, Homer Fogle, Tammy Price-Troska, Gregory Ahmann, Catherine Mancini, Leslie A. Brents, Shaji Kumar, Philip GreippAngela Dispenzieri, Barb Bryant, George Mulligan, Laurakay Bruhn, Michael Barrett, Riccardo Valdez, Jeff Trent, A. Keith Stewart, John Carpten, P. Leif Bergsagel

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

778 Scopus citations

Abstract

Activation of NF-κB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-κB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-κB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-κB pathway in the pathogenesis of multiple myeloma.

Original language	English (US)
Pages (from-to)	131-144
Number of pages	14
Journal	Cancer cell
Volume	12
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2007.07.003
State	Published - Aug 14 2007

Keywords

CELLCYCLE
SIGNALING

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2007.07.003

Cite this

Keats, J. J., Fonseca, R., Chesi, M., Schop, R., Baker, A., Chng, W. J., Van Wier, S., Tiedemann, R., Shi, C. X., Sebag, M., Braggio, E., Henry, T., Zhu, Y. X., Fogle, H., Price-Troska, T., Ahmann, G., Mancini, C., Brents, L. A., Kumar, S., ... Bergsagel, P. L. (2007). Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma. Cancer cell, 12(2), 131-144. https://doi.org/10.1016/j.ccr.2007.07.003

Keats, JJ, Fonseca, R , Chesi, M, Schop, R, Baker, A, Chng, WJ, Van Wier, S, Tiedemann, R, Shi, CX, Sebag, M, Braggio, E, Henry, T, Zhu, YX, Fogle, H, Price-Troska, T, Ahmann, G, Mancini, C, Brents, LA, Kumar, S, Greipp, P, Dispenzieri, A, Bryant, B, Mulligan, G, Bruhn, L, Barrett, M, Valdez, R, Trent, J, Stewart, AK, Carpten, J & Bergsagel, PL 2007, 'Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma', Cancer cell, vol. 12, no. 2, pp. 131-144. https://doi.org/10.1016/j.ccr.2007.07.003

@article{1981982ace194ee9970133c6c916519d,

title = "Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma",

abstract = "Activation of NF-κB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-κB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-κB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-κB pathway in the pathogenesis of multiple myeloma.",

keywords = "CELLCYCLE, SIGNALING",

author = "Keats, {Jonathan J.} and Rafael Fonseca and Marta Chesi and Roelandt Schop and Angela Baker and Chng, {Wee Joo} and {Van Wier}, Scott and Rodger Tiedemann and Shi, {Chang Xin} and Michael Sebag and Esteban Braggio and Travis Henry and Zhu, {Yuan Xiao} and Homer Fogle and Tammy Price-Troska and Gregory Ahmann and Catherine Mancini and Brents, {Leslie A.} and Shaji Kumar and Philip Greipp and Angela Dispenzieri and Barb Bryant and George Mulligan and Laurakay Bruhn and Michael Barrett and Riccardo Valdez and Jeff Trent and Stewart, {A. Keith} and John Carpten and Bergsagel, {P. Leif}",

note = "Funding Information: We are indebted to Warner C. Green and Robin J. Parks for so kindly providing the anti-p100/p52 antibody and AdRP2050 helper adenovirus. We would also like to thank the TGen Sequencing Core facility for their assistance with the DNA sequencing. We would also like to thank Paige Anderson, Aprill Watanabe, and Sandra Montgomery for their invaluable assistance. This work was supported by grants R01-AG020686 (P.L.B.), R01-CA83724-01 (R.F.), SPORE P50-CA100707-01 (R.F. and P.L.B.) and P01-CA62242 (R.F.) from the National Cancer Institute, and the Donaldson Charitable Trust Fund (R.F.). R.F. is a Clinical Investigator of the Damon Runyon Cancer Research Fund. L.B. is an Agilent Biosciences employee. M.B. is a former Agilent Biosciences employee. B.B. and G.M. are employees of Millennium Pharmaceuticals. R.F. has a consulting agreement with Millennium Pharmaceuticals. ",

year = "2007",

month = aug,

day = "14",

doi = "10.1016/j.ccr.2007.07.003",

language = "English (US)",

volume = "12",

pages = "131--144",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

AU - Keats, Jonathan J.

AU - Fonseca, Rafael

AU - Chesi, Marta

AU - Schop, Roelandt

AU - Baker, Angela

AU - Chng, Wee Joo

AU - Van Wier, Scott

AU - Tiedemann, Rodger

AU - Shi, Chang Xin

AU - Sebag, Michael

AU - Braggio, Esteban

AU - Henry, Travis

AU - Zhu, Yuan Xiao

AU - Fogle, Homer

AU - Price-Troska, Tammy

AU - Ahmann, Gregory

AU - Mancini, Catherine

AU - Brents, Leslie A.

AU - Kumar, Shaji

AU - Greipp, Philip

AU - Dispenzieri, Angela

AU - Bryant, Barb

AU - Mulligan, George

AU - Bruhn, Laurakay

AU - Barrett, Michael

AU - Valdez, Riccardo

AU - Trent, Jeff

AU - Stewart, A. Keith

AU - Carpten, John

AU - Bergsagel, P. Leif

N1 - Funding Information: We are indebted to Warner C. Green and Robin J. Parks for so kindly providing the anti-p100/p52 antibody and AdRP2050 helper adenovirus. We would also like to thank the TGen Sequencing Core facility for their assistance with the DNA sequencing. We would also like to thank Paige Anderson, Aprill Watanabe, and Sandra Montgomery for their invaluable assistance. This work was supported by grants R01-AG020686 (P.L.B.), R01-CA83724-01 (R.F.), SPORE P50-CA100707-01 (R.F. and P.L.B.) and P01-CA62242 (R.F.) from the National Cancer Institute, and the Donaldson Charitable Trust Fund (R.F.). R.F. is a Clinical Investigator of the Damon Runyon Cancer Research Fund. L.B. is an Agilent Biosciences employee. M.B. is a former Agilent Biosciences employee. B.B. and G.M. are employees of Millennium Pharmaceuticals. R.F. has a consulting agreement with Millennium Pharmaceuticals.

PY - 2007/8/14

Y1 - 2007/8/14

N2 - Activation of NF-κB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-κB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-κB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-κB pathway in the pathogenesis of multiple myeloma.

AB - Activation of NF-κB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-κB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-κB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-κB pathway in the pathogenesis of multiple myeloma.

KW - CELLCYCLE

KW - SIGNALING

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U2 - 10.1016/j.ccr.2007.07.003

DO - 10.1016/j.ccr.2007.07.003

M3 - Article

C2 - 17692805

AN - SCOPUS:34547660308

SN - 1535-6108

VL - 12

SP - 131

EP - 144

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

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Keywords

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