del(8p) and TNFRSF10Bloss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia

Autor: Jondreville, Ludovic, Dehgane, Lea, Doualle, Cecile, Smagghe, Luce, Grange, Beatrice, Davi, Frederic, Lerner, Leticia K., Garnier, Delphine, Bravetti, Clotilde, Tournilhac, Olivier, Roos-Weil, Damien, Boubaya, Marouane, Chapiro, Elise, Susin, Santos A., Nguyen-Khac, Florence
Zdroj: Leukemia; November 2023, Vol. 37 Issue: 11 p2221-2230, 10p
Abstrakt: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, the prognosis of which varies according to the cytogenetic group. We characterized a rare chromosomal abnormality (del(8p), deletion of the short arm of chromosome 8) in the context of CLL. By comparing the largest cohort of del(8p) CLL to date (n= 57) with a non-del(8p) cohort (n= 155), del(8p) was significantly associated with a poor prognosis, a shorter time to first treatment, worse overall survival (OS), and a higher risk of Richter transformation. For patients treated with fludarabine-based regimens, the next-treatment-free survival and the OS were shorter in del(8p) cases (including those with mutated IGHV). One copy of the TNFRSF10Bgene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10Bwas haploinsufficient in del(8p) CLL, and was involved in the modulation of fludarabine-induced cell death - as confirmed by our experiments in primary cells and in CRISPR-edited TNFRSF10Bknock-out CLL cell lines. Lastly, del(8p) abrogated the synergy between fludarabine and TRAIL-induced apoptosis. Our results highlight del(8p)’s value as a prognostic marker and suggest that fit CLL patients (i.e. with mutated IGHV and no TP53disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.
Databáze: Supplemental Index
Externí odkaz: