Homo sapiens Raw sequence reads for MYC dysregulation in the progression of multiple myeloma. Homo sapiens

To study the role of MYC in myeloma we performed an integrated genomic analysis of more than 600 newly diagnosed myeloma (NDMM) patients enrolled in the CoMMpass study, as well as targeted sequencing of 23 patients with monoclonal gammopathy of undetermined significance (MGUS) and 90 patients with smoldering myeloma (SMM). We found that MYC structural variants (MYC SVs) are absent from MGUS, but present in a quarter of SMM and in over 40% of NDMM. Nearly all NDMM with MYC SVs were found to have elevated mono-allelic MYC expression, while those without MYC SV had variable levels of bi-allelic MYC expression. Uniquely among the latter, there was a linear correlation between the level of MYC expression and the level of activation of the NFB pathway. The few patients lacking significant MYC expression had frequent inactivation of its heterodimeric partner MAX, a dominant negative tumor suppressor of the MYC pathway. Altogether in NDMM, MYC dysregulation is caused in two-thirds of patients by a genetic mutation and in half of the remaining patients by ligand-dependent NFB activation. This supports a model of plasma cell neoplasia in which MYC dysregulation is major mechanism by which tumor cells become less dependent on the bone marrow microenvironment.