The impact of SF3B1 mutations in CLL on the DNA-damage response
| Authors | |
|---|---|
| Year of publication | 2015 |
| Type | Article in Periodical |
| Magazine / Source | Leukemia |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2014318a.html |
| Doi | http://dx.doi.org/10.1038/leu.2014.318 |
| Field | Oncology and hematology |
| Keywords | CHRONIC LYMPHOCYTIC-LEUKEMIA; DOUBLE-STRAND BREAKS; MYELODYSPLASTIC SYNDROMES; SPLICING FACTOR; TP53 MUTATION; FREE SURVIVAL; CANCER GENES; ATM; PATHWAY; FLUDARABINE |
| Attached files | |
| Description | 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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