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Oquendo et al. J Transl Genet Genom 2021;5:89-111 https://dx.doi.org/10.20517/jtgg.2021.04 Page 95

Figure 2. Main pathways targeted by somatic mutations in SMZL. Recurrently mutated genes in SMZL preferentially target
physiologically important pathways, including the Notch pathway, chromatin remodelling, cell cycle control and canonical and non-
canonical NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. NF-κB can be activated through BCR, TLR
and BAFF-R signalling. Genes encoding proteins in grey have a mutational frequency greater than 10% within SMZL cohorts. SMZL:
Splenic marginal zone lymphoma; BCR: B-cell receptor; TLR: toll-like receptor; BAFF-R: B-cell activating factor receptor.

that it is predicted to be the 0.1% most deleterious substitutions you can do to the human genome. KLF2
mutations are early, clonal events, enriched in patients with deletions of 7q and IGHV1-2*04 gene usage and
are associated with a short median time to first treatment in univariate survival analysis .
[24]

NOTCH2 mutations occur in 10%-25% of cases
In murine models, and to a lesser extent in humans also, NOTCH2 plays a key role in MZ B-cell maturation
and MZ retention [66-69] . NOTCH2 is a cell-surface receptor belonging to a family of evolutionarily conserved
trans-membrane proteins. Notch pathways regulate cell proliferation, cell fate, differentiation, and cell
death . When a ligand binds to the extracellular domain of a Notch receptor, it initiates a cascade of
[70]
proteolytic cleavages that lead to the detachment of the notch intracellular domain, which then moves into
the nucleus to interact with target transcription factors [70,71] . NOTCH2 is the second most frequently mutated
gene present in 10%-25% of SMZL cases [23,24,54,56,72] . In SMZL, NOTCH2 mutations target the C-terminal
PEST domain on exon 34 , necessary for the regulation of the intracellular domain and consequent
[53]