Abstract
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 γH2AX 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.
Original language | English |
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Pages (from-to) | 1133-42 |
Number of pages | 10 |
Journal | Leukemia |
Volume | 29 |
Issue number | 5 |
Early online date | 5 Nov 2014 |
DOIs | |
Publication status | Published - May 2015 |
Keywords
- Apoptosis
- Ataxia Telangiectasia Mutated Proteins
- Cohort Studies
- DNA Damage
- DNA Mutational Analysis
- Doxorubicin
- Flow Cytometry
- Gene Deletion
- Gene Expression Regulation, Leukemic
- Genome, Human
- Histones
- Humans
- Imidazoles
- Leukemia, Lymphocytic, Chronic, B-Cell
- Mutation
- Phosphoproteins
- Piperazines
- Prognosis
- Receptor, Notch1
- Ribonucleoprotein, U2 Small Nuclear
- Tumor Suppressor Protein p53
- Vidarabine