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

GD. Te Raa, IA. Derks, V. Navrkalova, A. Skowronska, PD. Moerland, J. van Laar, C. Oldreive, H. Monsuur, M. Trbusek, J. Malcikova, M. Lodén, CH. Geisler, J. Hüllein, A. Jethwa, T. Zenz, S. Pospisilova, T. Stankovic, MH. van Oers, AP. Kater, E. Eldering,

. 2015 ; 29 (5) : 1133-1142. [pub] 20141105

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc15031749

Grantová podpora
NT13519 MZ0 CEP - Centrální evidence projektů

Digitální knihovna NLK
Plný text - Článek
Zdroj

E-zdroje NLK Online Plný text

ProQuest Central od 2000-01-01 do Před 1 rokem
Open Access Digital Library od 1997-01-01
Medline Complete (EBSCOhost) od 1997-01-01 do 2015-11-30
Nursing & Allied Health Database (ProQuest) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy
PubMed 25371178
DOI 10.1038/leu.2014.318
Knihovny.cz E-zdroje

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.

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$a 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.
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