Epigenetic silencing affects L-asparaginase sensitivity and predicts outcome in T-ALL

Purpose: Biological explanations for discrepancies in patients related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1 or TLX3 deregulated T-ALLs (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 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 Asparagine Synthetase (ASNS) when compared to 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 EFS (HR, 0.42 [95% CI, 0.24 to 0.71], p=0.001) and OS (HR, 0.40 [95% CI, 0.23 to 0.70], p=0.02) in 160 GRAALL2003/2005 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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