Saturday, May 17, 2025
5/17/2025
Myeloma Defining Genomic Events to Differentiate Benign and Malignant Myeloma Precursor Conditions - TITLE: Myeloma Defining Genomic Events to Differentiate Benign and Malignant Myeloma Precursor Conditions Cancer genetic study section: https://public.csr.nih.gov/StudySections/DBIB/OBT/CG ABSTRACT Multiple myeloma (MM) is the second most frequent hematological cancer, and its life-history is characterized by a progressive evolution from asymptomatic precursor stages (i.e., monoclonal gammopathy of undetermined significance and smoldering myeloma) to symptomatic disease. While these myeloma precursor conditions (MPC) are found in 3-5% of the adult population, only a small fraction will ultimately progress to MM. The ability to identify high-risk patients before major clonal expansion and symptoms arise has the potential to enable strategies of early prevention, which currently represents one of the most important unmet clinical needs. In the last four years, our group has shown for the first time that bulk whole genome sequencing (WGS) is the only technology able to comprehensively identify the key MM defining genomic events such as chromothripsis, APOBEC mutational activity, mutations in distinct driver genes. These events are emerging as critical to differentiate progressive from stable MPC. Despite its comprehensive resolution, bulk WGS has intrinsic limitations in defining small subclones, which often drive the MPC progression into MM. This limitation also affects our understanding of the early disease life-history and the early identification of MPC destined to progress. To overcome this, we have successfully explored a novel single-cell WGS platform (direct library preparation; DLP+) to fully characterize the subclonal genomic complexity and plasticity in each phase of MM evolution. Thanks to this unprecedent resolution combined with single cell RNA of the immune microenvironment, this study will allow to comprehensively define the clinical impact of MM defining genomic and immune events among MPC, allowing to differentiate benign from malignant entities. Among the key MM defining genomic events APOBEC mutational activity is the most prevalent and its presence is emerging as one of the most sensitive prognostic features for MPC progression, being detectable by bulk WGS in virtually all MM and in 80% of progressive patients, but absent among the stable ones. Despite its importance, it remains unclear whether APOBEC mutagenesis represents a genuine driver that promotes genomic instability and mutations in driver genes, or if it is merely an epiphenomenon of genomic instability and transformation. Considering that MM evolution is spread across decades, it is impossible to define when APOBEC starts its aberrant mutational activity during MM and MPC pathogenesis. To overcome this limitation, our group has interrogated the genomic landscape of the immunocompetent Vk*MYC mouse model known to spontaneously develop MM over 12-18 months. Spontaneous APOBEC mutational activity was detected in ~50% of the mice, making the Vk*MYC mouse the first immunocompetent model of cancer where it is possible to investigate the spontaneous APOBEC mutational activation. Exploring longitudinally with scWGS DLP+ the progressive expansion of clonal plasma cells in the Vk*MYC mouse model and combining the Vk*MYC mouse with mouse models with constitutive and inducible APOBEC activity will allow to define the role of APOBEC activation in MPC progression into MM.
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