Mechanisms of Clonal Expansion: Mutations, Methylation, and ncRNA Networks From Monoclonal B‐Cell Lymphocytosis to Chronic Lymphocytic Leukemia

Monoclonal B-cell lymphocytosis (MBL) is a type of chronic lymphocytic leukemia (CLL) and offers a unique window into the initial stages of leukemogenesis. Even though the vast majority of MBL patients are clinically stable, a subgroup develops CLL, which highlights the significance of understanding the molecular processes that modulate this development. Recent developments in molecular genetics have shown recurrent NOTCH1, SF3B1, TP53, and ATM mutations that determine clonal dynamics and the development of disease. In a like manner, the epigenetic dysregulation, where DNA methylation patterns and chromatin remodeling are aberrant, plays a role in lineage plasticity and altered outlines of gene expression during the transition phase between MBL and CLL. The significant role of non-coding RNAs (ncRNAs) in this development is intensively highlighted by growing evidence. MicroRNAs (miR-15a/16-1, miR-34a, and miR-155) and long non-coding RNAs (DLEU2, MALAT1, NEAT1) control apoptosis, DNA damage response and immune signaling, and transcriptional networks involved in leukemogenesis, respectively. The circular RNA is involved as a sponge in competing endogenous RNA interactions and enhances oncogenic signaling. Combining genetic, epigenetics, and ncRNA signatures provides an attractive chance to optimize risk stratification of MBL, forecast progression to CLL and establish minimally invasive biomarkers in liquid biopsy format. Though the application of ncRNA-targeted therapeutics is mostly experimental, initial translational research indicates that there are lines along which molecularly guided therapy can be pursued. This review provides a synthesis of the existing knowledge of the molecular evolution of MBL to CLL with a special focus on the interactions between DNA modifications, epigenetic control, and ncRNA biology and outlines how these findings can be used to provide more accurate diagnostics, prognostication, and subsequent targeted treatment.