Pathogenesis of splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a distinct low grade B-cell lymphoma with an immunophenotype similar to that of splenic marginal zone B-cells. Like the normal splenic marginal zone B-cells, SMZLs also show variable features in somatic mutations of their rearranged immunoglobulin genes, with ∼90% of cases harbouring somatic mutations but at remarkably variable degrees, suggesting that SMZL may have multiple cell of origins, deriving from the heterogeneous B-cells of the splenic marginal zone. Notably, ∼30% of SMZLs show biased usage of IGHV1-2*04, with the expressed BCR being potentially polyreactive to autoantigens. Recent exome and targeted sequencing studies have identified a wide spectrum of somatic mutations in SMZL with the recurrent mutations targeting multiple signalling pathways that govern the development of splenic marginal zone B-cells. These recurrent mutations occur in KLF2 (20–42%), NOTCH2 (6.5–25%), NF-κB (CARD11 ∼7%, IKBKB ∼7%, TNFAIP3 7–13%, TRAF3 5%, BIRC3 6.3%) and TLR (MYD88 5–13%) signalling pathways. Interestingly, the majority of SMZL with KLF2 mutation have both 7q32 deletion and IGHV1-2 rearrangement, and these cases also have additional mutations in NOTCH2, or TNFAIP3, or TRAF3. There is a potential oncogenic cooperation among concurrent genetic changes, for example between the IGHV1-2 expressing BCR and KLF2 mutation in activation of the canonical NF-κB pathway, and between KLF2 and TRAF3 mutations in activation of the non-canonical NF-κB pathway. These novel genetic findings have provided considerable insights into the pathogenesis of SMZL and will stimulate the research in both normal and malignant marginal zone B-cells.