SF3B1 MUTATIONS IN CLL ARE ASSOCIATED WITH A DEFECTIVE DNA DAMAGE RESPONSE

Konference: 2014 19th Congress of the European Hematology Association - účast ČR

Kategorie: Maligní lymfomy a leukémie

Téma: Chronic lymphocytic leukemia and related disorders - Biology (Poster)

Číslo abstraktu: P856

Autoři: Eric Eldering, PhD; MD Doreen te Raa; Ingrid Derks; Mgr. Veronika Navrkalová; Anna Skowronska; Ceri Oldreive; Perry Moerland; RNDr. Jitka Malčíková, Ph.D.; MUDr. Martin Trbušek, PhD; Jennifer Hüllein; Alexander Jethwa; Prof. Dr. med. Thorsten Zenz; prof. RNDr. Šárka Pospíšilová, Ph.D.; MD Tatjana Stankovic, PhD; MD Marinus H.J. Van Oers, PhD; MD Arnon P. Kater, PhD

ABSSUB-5021

Background: 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 ATMaberrations, suggesting functional synergy.

Aims: To uncover the mechanism underlying the contribution of SF3B1 mutation to CLL pathogenesis.

Methods: Detailed genetic and sequence analyses were done in a CLL cohort (n=105) containing ATMSF3B1and TP53 gene defects. Functional analyses were performed: a) p53/ATM target gene induction by multiplex assay, b) apoptosis responses to irradiation and chemotherapeutics, and c) γH2AX focus formation as marker for DNA damage by FACS and microscopy.

Results: There was considerable overlap between ATM and SF3B1 lesions; 18/29 of SF3B1 mutated cases carried concurrent 11q deletion and/or ATM mutation. Combined TP53 and SF3B1 mutations were found in 3/29 cases. In this report, we focus on the ten patients where single SF3B1 lesions were  identified.

Functionally, the single SF3B1 (sSF3B1) mutated samples resembled ATM mutated CLL in displaying defective ATM/p53 transcriptional and apoptosis response to various DNA-damaging regimens (Fig1A). In ATM mutated cases, sensitivity to fludarabine can be restored by nutlin-3a. This was also found for sSF3B1 mutations (Fig1B), although ATM kinase function remained intact. Finally, γH2AX formation was increased both at baseline and upon irradiation in SF3B1 mutated cases. The observed effects could not be explained by defective splicing of ATM inSF3B1 mutated cases.

Summary/Conclusion: Our data demonstrate that single mutations in SF3B1 are associated with increased DNA damage and/or aberrant response to DNA damage. Combined, our observations suggest an explanation for the poor prognosis of affected patients, and may lead to new treatment strategies

Keywords: Apoptosis, ATM, Chemoresistance, DNA damage

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Datum přednesení příspěvku: 14. 6. 2014