In the laboratory of Dr. Fonseca, we concentrate on the genetic and cytogenetic nature of the clonal cells of the plasma cell disorders. To achieve this, we use a variety of tools: molecular genetics, FISH, PCR, gene expression profiling, array based CGH, high throughput sequencing and others. Our laboratory currently is composed of seven full time technologists and three post-doctoral fellows.

Origin of the MGUS and myeloma clone: 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. Our laboratory was the first two describe that the two main pathways in myeloma pathogenesis, hyperdiploid vs non-hyperdiploid is dictated by the presence of IgH translocations. Furthermore, we were the first to show that this dichotomy is existent since MGUS. Our lab was among the first to describe the presence of the same genetic abnormalities in MGUS as we see in myeloma, including the high-risk genetic features.

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 are studying how the acquisition of other genetic factors may lead to progression including the newly described aberrations resulting in NF-kB activation.

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. Our lab was the first to show the clinical implications of the high-risk genetic translocations including the t(4:14) and t(14;16). This information is now included in what the myeloma community calls high-risk myeloma. Many medical centers do not proceed to autologous stem cell transplant for patients with high-risk myeloma. Our studies have been converted into a clinical test available from Mayo Medical Laboratories.

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 chormosome 6 in nearly half of patients with WM. We also showed these cells lack chromosome translocations and never have the t(9;14), resulting in PAX5 upregulation.