Abstract
Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow and belongs to the mature B-cell neoplams. The pathogenesis of MM is associated with constitutive NF-κB activation. However, genetic alterations causing constitutive NF-κB activation are still incompletely understood. Since A20 (TNFAIP3) is a suppressor of the NF-κB pathway and is frequently inactivated in various lymphoid malignancies, we investigated the genetic and epigenetic properties of A20 in MM. In total, of 46 patient specimens analyzed, 3 single base pair exchanges, 2 synonymous mutations and one missense mutation were detected by direct sequencing. Gene copy number analysis revealed a reduced A20 gene copy number in 8 of 45 (17.7%) patients. Furthermore, immunohistochemical staining confirmed that A20 expression correlates with the reduction of A20 gene copy number. These data suggest that A20 contributes to tumor formation in a significant fraction of myeloma patients.
Highlights
Multiple myeloma (MM) is a monoclonal tumor of bone marrow (BM) plasma cells, characterized by the presence of monoclonal immunoglobulins in blood and urine in a majority of cases, and is frequently associated with organ dysfunction [1]
Molecular studies revealed the expression of constitutively active NF-kB in bone marrow aspirates in the majority of myeloma patients [3,4]
46 myeloma patient specimens were analyzed by direct sequencing
Summary
Multiple myeloma (MM) is a monoclonal tumor of bone marrow (BM) plasma cells, characterized by the presence of monoclonal immunoglobulins in blood and urine in a majority of cases, and is frequently associated with organ dysfunction [1]. Molecular studies revealed the expression of constitutively active NF-kB in bone marrow aspirates in the majority of myeloma patients [3,4]. The clinical use of bortezomib-a proteasome inhibitor known to inhibit NF-κB—in the treatment of myeloma, demonstrates the importance of the constitutive activation of the NF-κB-pathway in the pathogenesis of myeloma [5,6]. The identification of mutations in NF-κB regulators in 17% of MM patients shed some light on the mechanisms responsible for the constitutive NF-κB activation, other genetic alterations involved in this pathway are still incompletely understood [7,8,9].
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