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CHRONIC LYMPHOCYTIC LEUKEMIA

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

Leukemia volume 37, pages 2221–2230 (2023)Cite this article

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Abstract

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.

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Fig. 1: Constitution of two groups of patients as a function of the size of del(8p), with intergroup differences in survival.
Fig. 2: Survival of del(8p) vs. non-del(8p) patients.
Fig. 3: TNFRSF10B is downregulated in del(8p) cells compared to non-del(8p) CLL cells.
Fig. 4: Inactivation of TNFRSF10A and TNFRSF10B induces resistance to TRAIL in the OSU-CLL cell line.
Fig. 5: Fludarabine treatment induces TNFRSF10B expression in primary non-del(8p) CLL cells but del(8p) specifically abrogates the decrease in cell viability induced by the fludarabine-TRAIL combination.
Fig. 6: del(8p) abolishes fludarabine-induced p53-dependent gene expression.

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Data availability

Data are available within the manuscript, figures, or supplementary information. The datasets generatedand/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The present research was funded by Roche Diagnostics, Force Hemato (grant reference: 03–2022), French Innovative Leukemia Organization (FILO) group, ACLF (grant 2022) and SIRIC-CURAMUS (Cancer United research Associating Medecine, University and Society; grant reference: INCa-DGOS-INSERM_12560 and INCa-DGOS-INSERM-ITMO Cancer_18010). L.J. and L.D. received PhD fellowships from Fondation ARC and SIRIC-CURAMUS, respectively. L.K.L. received postdoctoral fellowships from Fondation ARC and Fondation de France. L.S. was funded by the FILO group and the SIRIC-CURAMUS. We thank M Yon, E Pramil and C Gabillaud for preliminary assessments. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors jointly supervised this work: Elise Chapiro, Santos A. Susin, Florence Nguyen-Khac.

Authors and Affiliations

  1. Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS 1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France

    Ludovic Jondreville, Lea Dehgane, Cecile Doualle, Luce Smagghe, Frederic Davi, Leticia K. Lerner, Delphine Garnier, Clotilde Bravetti, Damien Roos-Weil, Elise Chapiro, Santos A. Susin & Florence Nguyen-Khac

  2. Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Sorbonne Université, AP-HP, Paris, France

    Beatrice Grange, Frederic Davi, Clotilde Bravetti, Elise Chapiro & Florence Nguyen-Khac

  3. Service d’Hématologie Clinique, CHU Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand, France

    Olivier Tournilhac

  4. Service d’Hématologie Clinique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France

    Damien Roos-Weil

  5. Unité de Recherche Clinique, Hôpitaux Universitaires Paris Seine-Saint-Denis, AP-HP, Bobigny, France

    Marouane Boubaya

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Contributions

FN-K. and SAS designed the study. LJ and EC performed experiments and analyzed data. LD, CD, LS, BG, FD, LKL, DG, CB performed experiments. OT and DR-W provided samples and clinical data. MB performed statistical analyses. FN-K, SAS, EC and LJ wrote the manuscript.

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Correspondence to Elise Chapiro, Santos A. Susin or Florence Nguyen-Khac.

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Jondreville, L., Dehgane, L., Doualle, C. et al. del(8p) and TNFRSF10B loss are associated with a poor prognosis and resistance to fludarabine in chronic lymphocytic leukemia. Leukemia 37, 2221–2230 (2023). https://doi.org/10.1038/s41375-023-02035-3

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