AL MODELS AND CLINICAL TRIALS

Beyond our basic science interests in AL, we also have a heavy emphasis on translational research components utilizing the collaborative and clinical infrastructure of the Mayo Clinic. To this end, we have ongoing projects in several diverse areas that collectively will support future endeavors transforming our basic science understanding of AL proteins allowing us to develop better diagnosis and therapeutic strategies.

A team of Mayo researchers led by Dr. Diane Jelinek has recently published the establishment of two cell lines derived from an AL patient, the first successful AL cell line ever reported. Using a comprehensive genetic approach, the genetic relationship between the cell lines and the primary patient cells was established allowing identification of genetic changes accompanying tumor progression that may explain the natural history of this patient’s disease. Importantly, we demonstrate that free lambda LC secreted by both cell lines had an immunoglobulin fold (β-sheet barrel) and formed amyloid fibrils. These cell lines will provide an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology.

In a natural follow on to cellular studies and to examine the complex processes of AL there are efforts in our laboratory to establish an AL zebrafish model system. The zebrafish (Danio rerio) is the premier non-mammalian vertebrate model organism. This small fish is being utilized by over a thousand laboratories around the world because of its biological similarity to humans, its advanced molecular genetics, the elucidation of its genome sequence, and the ever-expanding and outstanding new biological tools now available to the zebrafish researcher.

The culmination of all of our research is ultimately to improve treatment options for AL patients through increased understanding of the disease process. To this end we are also involved in Clinical trials within the Mayo Clinic. The study that we are currently involved addresses whether patients with AL receiving high dose therapy in combination with stem cell transplant have superior response rates to those treated with more conventional chemotherapy. We are combining this with a study of the specific B-cell characteristics and immunoglobulin light chain misfolding kinetics to understand if there is a correlation between the B-cell biology and protein misfolding with their clinical outcome.