Table 2. Mutations involving the B-cell pathways in MCL.

Gene	Site/pathway	Result of mutation	Associated somatic mutation	Potential therapeutic strategy
C418S	BTK	Persistent activation of BTK and AKT (ibrutinib resistance)	CCND1	Palbociclib (inhibition of CDK4) plus Ibrutinib
NOTCH1	PEST domain/NOTCH pathway	Phosphorylation and ubiquitylation of multiple sites of NOTCH intracellular domain; activation of transcription of downstream genes
BIRC2	Somatic/NF-KB pathway	Activation of the alternate NF-KB pathway (possible mechanism of ibrutinib resistance)
BIRC3	Somatic/NF-KB pathway	Activation of the alternate NF-KB pathway and direct effect on cells (possible mechanism of ibrutinib resistance)
TRAF2/TRAF3	Somatic/NF-KB pathway	Activation of the alternate NF-KB pathway (possible mechanism of resistance)
NIK (MAP3K14)	BCR pathway	Activation of the alternate NF-KB pathway (possible mechanism of ibrutinib resistance)	BIRC2/TRAF3	Ibrutinib plus NIK inhibitor