Identification of copy-number abnormalities and inactivating mutations in two negative regulators of NF-kB signaling pathways in Waldenström’s Macroglobulinemia

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 8; pp. 3579 - 3588
• Main Authors: Braggio, Esteban, Keats, Jonathan J, Leleu, Xavier, Van Wier, Scott, Jimenez-Zepeda, Victor H, Valdez, Riccardo, Schop, Roelandt FJ, Price-Troska, Tammy, Henderson, Kimberly, Sacco, Antonio, Azab, Feda, Greipp, Philip, Gertz, Morie, Hayman, Suzanne, Rajkumar, S Vincent, Carpten, John, Chesi, Marta, Barrett, Michael, Stewart, A Keith, Dogan, Ahmet, Bergsagel, P Leif, Ghobrial, Irene M, Fonseca, Rafael
• Format: Journal Article
• Language: English
• Published: 07.04.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3701

Waldenström’s macroglobulinemia (WM) is a distinct clinico-biological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow (BM) and immunoglobulin M paraprotein production. Cytogenetic analyses were historically limited by the 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 high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of patients 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 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3 , two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the BM microenvironment, highlights its biologic importance, and suggests a therapeutic role for inhibitors of NF-kB pathway activation in the treatment of Waldenström’s macroglobulinemia.