fig5

Figure 5. Current state of SMZL knowledge, proposed strategies, and future perspectives. The upper orange box highlights current knowledge in SMZL. The diagram outlines key areas for future research starting with unbiased whole genome sequencing of matched germline-tumour samples across the disease history. Each time point will allow for the identification of key immunogenetic and cytogenetic subgroups, as well as mutational signatures. Whole genome sequencing is essential for the identification of non-coding mutations, and with large collaborative cohorts enabling the identification of SNPs associated with disease risk. This unbiased approach will form the basis for more targeted studies, analysing additional contributory factors such as epigenome of SMZL and telomere attrition mechanisms. The identification and analysis of suitable control MZ B-cells will be important work that will feed into wider studies, particularly epigenetic studies and determining the cell of origin. Synthesis of new information will allow the identification of biological sub-groups and direct downstream functional analyses. The ultimate goal is to translate newly acquired knowledge of the underlying molecular mechanism of SMZL for direct patient benefit: to improve differential diagnosis and aid in the discovery of novel therapeutic targets. SMZL: Splenic marginal zone lymphoma; MZ: marginal zone; CNAs: copy number alterations; WGS: whole genome sequencing; CBL-MZ: clonal B cell lymphocytosis of marginal zone origin; IGHV: immunoglobulin heavy chain variable region; FACS: fluorescence-activated cell sorting; TME: tumour microenvironment.