The impact of SF3B1 mutations in CLL on the DNA-damage response
2015
Mutations or deletions in TP53 or ATM are well-known
determinants of poor prognosis in chronic lymphocytic leukemia
(CLL), but only account for approximately 40% of
chemo-resistant patients. Genome-wide sequencing has uncovered
novel mutations in the splicing factor sf3b1, that were in part
associated with ATM aberrations, suggesting functional synergy.
We first performed detailed genetic analyses in a CLL cohort
(n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we
applied a newly developed multiplex assay for p53/ATM target
gene induction and measured apoptotic responses to DNA damage.
Interestingly, SF3B1 mutated samples without concurrent ATM and
TP53 aberrations (sole SF3B1) displayed partially defective
ATM/p53 transcriptional and apoptotic responses to various
DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated
CLL displayed normal responses in p53/ATM target gene induction
and apoptosis. In sole SF3B1 mutated cases, ATM kinase function
remained intact, and gamaH2AX formation, a marker for DNA
damage, was increased at baseline and upon irradiation. Our
data demonstrate that single mutations in sf3b1 are associated
with increased DNA damage and/or an aberrant response to DNA
damage. Together, our observations may offer an explanation for
the poor prognosis associated with SF3B1 mutations
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