SF3B1 and B-cell chronic lymphocytic leukemia: In summary, the work presented here reports (1) the first generation of isogenic genome–edited CLL cell lines differing only by the presence or absence of a single amino acid substitution in SF3B1, (2) the identification of a wider variety of 3′ splice site activation events upon SF3B1 mutation compared with previous reports, (3) provides evidence that the SF3B1 inhibitor H3B-8800 displays therapeutic effects in mouse models of CLL, particularly when used on CLL cells harboring SF3B1 mutations, and (4) provides evidence of synergism between a SF3B1-targeting drug and venetoclax.