Molecular Mechanisms in the Transformation from Indolent to Aggressive B Cell Malignancies

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL). The most common histologic subtype resulting from HT is diffuse large B cell lymphoma (DLBCL). Consistently, DLBCL arisen from indolent non-Hodgkin lymphomas still represents an unmet clinical need, due to disease aggressiveness and resistance to available treatment approaches. Numerous molecular alterations associated with the occurrence of the aggressive HT of CLL (known as Richter transformation) have been identified, namely, genetic lesions of TP53, CDKN2A, NOTCH1, and c-MYC, dysregulation of immune checkpoints, and hyperactivation of the B cell receptor pathway. HT of FL involves a combination of genetic and epigenetic alterations affecting genes involved in cell-cycle control (e.g., CDKN2A/B), DNA damage response (e.g., TP53 and BCL6), proliferation including the NF-κB pathway, and microenvironmental interactions (namely, TNFSRF14). The molecular pathways driving MZL transformation include copy number alterations, mutations of NOTCH2, KLF2, TNFAIP3, KMT2D, and FOXP1, as well as epigenetic dysregulation. The molecular alterations underlying the aggressive transformation of LPL are poorly understood, with CXCR4 mutations being the primary factor involved. Current knowledge of the molecular mechanisms of HT has led to promising therapeutic strategies targeting immune checkpoints, BCL2, and BTK, and exploiting bispecific monoclonal antibodies and chimeric antigen receptor (CAR)-T cells. Further investigations are necessary for a deeper understanding of the molecular mechanisms underlying HT, in order to further highlight predictive biomarkers of transformation and develop effective treatment strategies. The aim of this review is to provide a comprehensive overview of the molecular mechanisms that drive transformation to DLBCL of CLL, FL, MZLs, and LPL.