del(8p) and TNFRSF10B loss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia

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...

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Veröffentlicht in:Leukemia 2023-11, Vol.37 (11), p.2221-2230
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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 TNFRSF10B gene (coding a pro-apoptotic receptor activated by TRAIL) was lost in 91% of del(8p) CLL. TNFRSF10B was 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 TNFRSF10B knock-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 TP53 disruption) should be screened for del(8p) before the initiation of fludarabine-based treatment.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-023-02035-3