Monoclonal gammopathy of undetermined significance (MGUS) results from a benign clonal bone marrow plasma cell expansion. It progresses to multiple myeloma (MM) at a rate of about 1% per year. We have implicated genetic dysregulation of MYC as one likely cause of this progression based on three key findings: 1) the major difference in expression between MGUS and MM is the increased expression of MYC, 2) the MYC locus is mutated in half of untreated patients with MM, making it the most frequent single mutation in MM, and 3) introduction of a MYC transgene into a strain of mouse that spontaneously develops monoclonal gammopathy, but not into one that does not, results in mice that uniformly develop MM. In this proposal we aim to study the clinical significance of MYC rearrangements and determine if they represent a marker that can distinguish benign clonal plasma cells from malignant clonal plasma cells. And if they can identify MM patients with a different response to lenalidomide, a drug that leads to a cerebron-dependent down regulation of IRF4 and MYC. Finally we will explore the significance of obtaining a partial response to treatment, comparing the cells remaining after therapy to those taken before therapy was initiated.
A genetic rearrangement of the MYC locus is the most common mutation in multiple myeloma. We will determine the clinical significance of this mutation, and study the effect of lenalidomide (that inhibits MYC transcription) on MM cells with MYC rearrangements.
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