In the Fonseca laboratory we are interested in understanding the genetic events that lead to multiple myeloma, a type of bone marrow cancer. To achieve this, we use a variety of tools: Molecular genetics, Fluorescent in situ hybridization (FISH), Array comparative genomic hybridization (aCGH) and Global expression profiling (GEP). We believe that myeloma development is best understood by the study of monoclonal gammopathy of undetermined significance (MGUS). The MGUS to myeloma progression model allow us to understand factors important in initiating, maintaining and transforming a benign pre-cancerous condition (MGUS) to the cancerous stage of the disease (myeloma). We are primarily focused on the:
Origin of the MGUS clone and genomic instability:
We have begun a systematic evaluation of MGUS plasma cells by molecular/cytogenetic methods. Ultimately we want to understand the nature of the clone, clinical and biologic significance of the abnormalities, and order of acquisition of abnormalities. We are also interested in the factors permissive for the significant genomic instability observed in the plasma cell neoplasms. One such example is centrosome amplification.
Progression from MGUS to myeloma:
We want to better understand why some MGUS patients progress to MM and why some never do, and which abnormalities are acquired and thus important for disease progression. In the context of a funded SPORE grant we are doing a detailed genetic characterization of the risk of progression in MGUS according to cytogenetic status. We also described the presence of these IgH translocations in MGUS cells, even those associated with an aggressive clinical behavior in myeloma. Most recently we have shown the presence of hyperdiploid and Non-hyperdiploidy dichotomy in MGUS.
Clinical significance of chromosomal abnormalities in myeloma:
In our lab we study the clinical, biologic, and prognostic implications of specific chromosomal and genetic abnormalities for patients with myeloma.
Ultimately, we believe that the accurate knowledge of the abnormalities underlying myeloma will allow for a better management and treatment of patients. For instance we have described the negative impact on prognosis of some genetic aberrations and better outcome with others. Furthermore we have shown different pathology and clinical features of myeloma based on this genetic characterization. Recently, we have performed a series of studies to comprehensively characterize hyperdiploid myeloma, the most common genetic subtypes of myeloma, and have identified new prognostically important subtypes.
Molecular studies of genetic abnormalities in clonal cells of light-chain amyloidosis:
Ultimately, we want to understand the nature of the clone, and its relation to the protein abnormality. We also have interest in the features of the light chains that make them amyloidogenic.
Molecular studies of genetic abnormalities in clonal cells of Waldenstrom macroglobulinemia (WM):
Our studies have focused on the genetic abnormalities of clonal cells of patients with macroglobulinemia and their relation to other B-cell malignancies. Our lab described the presence of losses in chromosome 6 in nearly one half of patients with WM and has shown these cells lack heavy chain translocations including the t(9;14), resulting in PAX5 up regulation.
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