Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL - Aix-Marseille Université Access content directly
Journal Articles Clinical Cancer Research Year : 2019

Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL

Charlotte Smith
Xavier Thomas
  • Function : Author
Thibaut Leguay
  • Function : Author
Carlos Graux
  • Function : Author
Yves Chalandon
Francoise Huguet
  • Function : Author
Stéphane Lepretre
  • Function : Author
Norbert Ifrah
  • Function : Author
  • PersonId : 992780
Hervé Dombret
  • Function : Author
  • PersonId : 1011921
Elizabeth Macintyre
  • Function : Author
  • PersonId : 902525
Nicolas Boissel
  • Function : Author
  • PersonId : 1033622
Vahid Asnafi
  • Function : Author
  • PersonId : 1033443

Abstract

Purpose: Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes.Experimental Design: We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples.Results: We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24-0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23-0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012).Conclusions: We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.
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Dates and versions

hal-02078351 , version 1 (27-03-2019)

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Aurore Touzart, Etienne Lengliné, Mehdi Latiri, Mohamed Belhocine, Charlotte Smith, et al.. Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL. Clinical Cancer Research, 2019, ⟨10.1158/1078-0432.CCR-18-1844⟩. ⟨hal-02078351⟩
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