The impact of SF3B1 mutations in CLL on the DNA-damage response

• Verfasst von: Raa, G. Doreen te [VerfasserIn]
• Verfasst von: Hüllein, Jennifer [VerfasserIn]
• Verfasst von: Jethwa, Alexander [VerfasserIn]
• Verfasst von: Zenz, Thorsten [VerfasserIn]
• Titel: The impact of SF3B1 mutations in CLL on the DNA-damage response
• Verf.angabe: G.D. te Raa, I.A.M. Derks, V. Navrkalova, A. Skowronska, P.D. Moerland, J. van Laar, C. Oldreive, H. Monsuur, M. Trbusek, J. Malcikova, M. Lodén, C.H. Geisler, J. Hüllein, A. Jethwa, T. Zenz, S. Pospisilova, T. Stankovic, M.H.J. van Oers, A.P. Kater and E. Eldering
• Jahr: 2015
• Jahr des Originals: 2014
• Umfang: 10 S.
• Fussnoten: Published online: 5 December 2014 ; Gesehen am 18.05.2017
• Titel Quelle: Enthalten in: Leukemia
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2015
• Band/Heft Quelle: 29(2015), 5, Seite 1133-1142
• ISSN Quelle: 1476-5551
• DOI: doi:10.1038/leu.2014.318
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1558783032

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.