# name
SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia

# metadata.dc.description.abstract[].value
Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA
branch site recognition and is the target of antitumor-splicing
inhibitors. Mutations in SF3B1 are observed in 15% of patients
with chronic lymphocytic leukemia (CLL) and are associated with
poor prognosis, but their pathogenic mechanisms remain poorly
understood. Using deep RNA-sequencing data from 298 CLL
tumor samples and isogenic SF3B1 WT and K700E-mutated CLL
cell lines, we characterize targets and pre-mRNA sequence
features associated with the selection of cryptic 39 splice sites
upon SF3B1 mutation, including an event in the MAP3K7 gene
relevant for activation of NF-κB signaling. Using the H3B-8800
splicing modulator, we show, for the first time in CLL, cytotoxic
effects in vitro in primary CLL samples and in SF3B1-mutated
isogenic CLL cell lines, accompanied by major splicing changes
and delayed leukemic infiltration in a CLL xenotransplant mouse
model. H3B-8800 displayed preferential lethality towards SF3B1-
mutated cells and synergism with the BCL2 inhibitor venetoclax,
supporting the potential use of SF3B1 inhibitors as a novel
therapeutic strategy in CLL.

# metadata.dc.publisher[].value
EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press

# metadata.dc.relation.ispartof[].value
Life Science Alliance, 2023, vol. 6, num.11

# metadata.dc.rights[].value
cc-by (c) López Oreja, Irene et al., 2023

# metadata.dc.source[].value
Articles publicats en revistes (Fonaments Clínics)

# metadata.dc.title[].value
SF3B1 mutation-mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic leukemia