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Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL
Aurore Touzart1, Etienne Lengliné2, Mehdi Latiri1
1Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de recherche Médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.
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.
Insights
Epigenetic silencing of asparagine synthetase (ASNS) in T-cell acute lymphoblastic leukemia (T-ALL) impacts patient outcomes. ASNS promoter methylation predicts l-asparaginase sensitivity and survival, guiding personalized chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- T-cell acute lymphoblastic leukemia (T-ALL) exhibits diverse patient responses to chemotherapy, influenced by underlying oncogenic events.
- TLX1- and TLX3-deregulated T-ALL subtypes share immature phenotypes but differ in prognosis, necessitating identification of key molecular determinants.
- Understanding these molecular differences is crucial for improving treatment strategies and patient outcomes.
Purpose of the Study:
- To investigate the molecular basis for differential patient outcomes in TLX1- and TLX3-deregulated T-ALL.
- To identify candidate genes, through transcriptomic analysis, that may explain the distinct clinical outcomes associated with TLX1+ and TLX3+ T-ALL.
- To evaluate the role of asparagine synthetase (ASNS) epigenetic regulation and its impact on l-asparaginase sensitivity.
Main Methods:
- Comparative analysis of adult T-ALL patient outcomes from French national multicentric trials (LALA-94, GRAALL-2003/2005).
- Transcriptomic data analysis to identify differentially expressed genes between TLX1+ and TLX3+ T-ALL.
- Evaluation of ASNS epigenetic regulation (DNA methylation, histone marks) and in vitro l-asparaginase sensitivity in T-ALL cell lines and primary samples.
Main Results:
- TLX1+ T-ALL patients exhibited significantly lower ASNS expression compared to TLX3+ and TLX-negative patients due to epigenetic silencing.
- ASNS promoter methylation correlated with reduced l-asparaginase sensitivity in T-ALL cell lines and patient-derived xenografts.
- ASNS promoter methylation was identified as an independent prognostic factor for event-free and overall survival in T-ALL patients and T lymphoblastic lymphomas.
Conclusions:
- ASNS methylation status at diagnosis is a potential biomarker for predicting treatment response in T-ALL.
- Individual adaptation of l-asparaginase dosage may be guided by ASNS methylation status.
- This finding offers a pathway towards more personalized chemotherapy strategies in T-ALL treatment.
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