One gene, two diseases: The pathologic role of IGLV1-44 in AL amyloidosis and POEMS

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023 The IGLV1-44 gene encodes immunoglobulin light chains (LCs) which are key components of antibodies. Like all immunoglobulin genes, IGLV1-44 can accumulate mutations, resulting in the production of IGLV1-44 LCs with variable composition. In the presence of an antibody-producing tumor, patients’ specific IGLV1-44 LCs can accumulate in the blood at abnormal levels. If IGLV1-44 LCs of a given patient turn out to be unstable, they aggregate and can cause severe and often incurable forms of cardiac light chain (AL) amyloidosis. The abundant presence of circulating IGLV1-44 LCs can also be associated with POEMS syndrome, another rare tumor. In both diseases LCs display strong toxicity triggering severe, life-threatening organ damage. At present, the specific characteristics of the IGLV1-44 LCs sequences that cause AL or POEMS are not known, preventing early diagnosis of these diseases. Furthermore, currently there is no available treatment to impair LC toxicity. This project aims to provide answers to these medical needs. A bioinformatic analysis on the largest database of IGLV1-44 LCs will identify the features specifically correlating with AL or POEMS. These LCs will be purified in the laboratory and characterized; importantly cellular and animal models will be used to verify their toxicity. Properties relevant for LC toxicity will be modified and the toxicity of such variants will be verified. These experiments will identify key features of IGLV1-44 LC sequences correlating with AL and POEMS. Furthermore, this project will develop proteins with therapeutic potential (nanobodies) that are able to specifically recognize pathological LCs and abolish their toxicity.