Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer [ATAC-seq]

Small cell lung cancer (SCLC) frequently harbors mutually exclusive genomic amplification of MYC family members. Therefore, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Integrated transcriptomic and epigenomic analyses showed that c-Myc and L-Myc impart neuronal and non-neuroendocrine associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc-SCLC induced a neuronal state but was insufficient to induce ASCL1 lineage. In contrast, c-Myc induced transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, we characterize an undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses. Overall design: Accessible chromatin and Myc accessible profile of six SCLC cell lines, NCI-H82 cells genetically engineered to overexpress L-Myc and ablate the expression of c-Myc with control and of NCI-H1963 genetically engineered cells to overexpress c-Myc with control.