Identification of copy-number abnormalities and inactivating mutations in two negative regulators of NF-kB signaling pathways in Waldenström’s Macroglobulinemia
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...
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Published in | Cancer research (Chicago, Ill.) Vol. 69; no. 8; pp. 3579 - 3588 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
07.04.2009
|
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/0008-5472.CAN-08-3701 |