Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-κB signaling pathways in Waldenström's macroglobulinemia

Esteban Braggio, Jonathan J. Keats, Xavier Leleu, Scott Van Wier, Victor H. Jimenez-Zepeda, Riccardo Valdez, Roelandt F.J. Schop, Tammy Price-Troska, Kimberly Henderson, Antonio Sacco, Feda Azab, Philip Greipp, Morie Gertz, Suzanne Hayman, S. Vincent Rajkumar, John Carpten, Marta Chesi, Michael Barrett, A. Keith Stewart, Ahmet DoganP. Leif Bergsagel, Irene M. Ghobrial, Rafael Fonseca

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Waldenström's macroglobulinemia (WM) is a distinct clinico-biological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13ql4 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor-associated factor 3 and TNFα-induced protein 3, two negative regulators of the nuclear factor-κB (NF-κB) signaling pathway. Furthermore, we confirmed the association between TBAF3 inactivation and increased transcriptional activity of NF-κB target genes. Mutational activation of the NF-κB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-κB pathway activation in the treatment of WM.

Original languageEnglish (US)
Pages (from-to)3579-3588
Number of pages10
JournalCancer research
Volume69
Issue number8
DOIs
StatePublished - Apr 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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