Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, is a malignancy of morphologically differentiated plasma B-cells and is largely incurable. Chromosome 13 deletions (del) are found in approximately one half (50%) of all patient samples and is associated with worse prognosis, but previous efforts have failed to conclusively identify the MM tumor suppressor gene on chromosome 13. We used a unique ultra high-resolution array comparative genomic hybridization (aCGH) platform to analyze MM patient samples, and identified neurobeachin (NBEA) as a novel target of recurrent interstitial deletions. NBEA encodes a protein kinase A anchoring protein (AKAP) that is localized to the trans-Golgi, transport vesicles and post-synaptic membranes of neurons where it plays a functional role in neuronal cell synaptic transmission. Our Preliminary Data demonstrated not only that NBEA is a target of chromosomal deletions at 13q13, but that NBEA expression at the RNA and protein level is significantly dysregulated in MM patient samples. Our hypothesis is that del contributes to dysregulation of the NBEA gene, and that NBEA over- expression contributes to MM disease progression. To determine the potential role of NBEA as a tumor marker in MM, we propose the following aims:
Aim 1 : Characterize the relationship between the NBEA gene and MM disease stage. We have assembled a unique MM tissue bank with both tumor and germline patient samples, and we will characterize the NBEA locus in depth in our MM patient samples. We will correlate NBEA genotypes and expression data with clinical patient data, and anticipate that NBEA genotypes will be associated with poor outcomes in MM.
Aim 2 : Develop novel assays for NBEA protein detection in MM patient samples. Quantitative detection of NBEA protein in MM clinical samples will provide a useful adjunct to nucleic acid based detection methods. We will correlate NBEA protein levels with clinical patient data, and anticipate that high NBEA protein expression will be associated with poor outcomes in MM.
Aim 3 : Establish the role of NBEA in MM disease progression. Genetically defined murine models will be used to definitively address the role of NBEA in myeloma development. Our long-term goal is to develop novel disease prevention strategies based on understanding the genetic contribution, both germline and somatic, to MM disease development.
Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States accounting for approximately 10% of all hematologic neoplasms. We have i) established a unique MM tissue bank to provide critical tools for genetic studies and ii) have developed a database to prospectively collect clinical data on MM patients seen at the Siteman Comprehensive Cancer Center, so that we can trace molecular abnormalities back to clinical outcomes. We have identified NBEA as a novel candidate gene on chromosome 13 that is targeted by interstitial deletions and whose expression is dysregulated. We will validate the role of NBEA in MM and will develop assays to characterize NBEA in MM clinical specimens.