In childhood patients with T-cell acute lymphoblastic leukemia (T-ALL) the hypomethylation status of the arginine synthetase (ASNS) gene was significantly associated with poor therapeutic outcome, according to the results of a Japanese cohort study published online in Blood Advances.
Researchers Koshi Akahane, PHD, of the University of Yamanashi, Kofu, Japan, and colleagues conducted a comprehensive genetic analysis of diagnostic samples of 22 cell lines from childhood patients with T-ALL in Japan.
They also correlated known methylation status with outcomes in two large patient cohorts of Japanese children with T-ALL: the Tokyo Children’s Cancer Study Group (n = 57) and the Japan Association of Childhood Leukemia Study Group (n = 20).
Methylation results
For the 22 cell lines tested, sequencing technology revealed a stepwise allele-specific methylation of the ASNS gene. Mean ASNS gene expression level was significantly upregulated in 14 weakly methylated cell lines (P = .0001), but not significantly upregulated in 3 intermediately methylated cell lines (P = .25) or in 5 highly methylated cell lines (P = .063).
Among the 77 patient cohorts, 20 (26%) samples showed high methylation (> 66.7%), while 15 (19%) samples and 42 (55%) samples showed intermediate (33.3%-66.7%) and weak (< 33.3%) methylation status, respectively.
For the 75 patients where information was provided on outcomes, 25 patients (33%) showed induction failure or disease relapse. A highly methylated status of the ASNS gene was significantly more common in non-refractory/relapse cases (18/50 cases, 36%), while intermediately or weakly methylated status was more common in refractory/relapsed cases (23/25 cases, 92 %; P = .0001). In a log-rank test, the patients with weakly methylated status of the ASNS gene showed significantly shorter event-free survival and overall survival than the patients with an intermediate or highly methylated status (P = .00012 and P = .00016, respectively).
Asparaginase sensitivity
Asparaginase treatment is a key component of chemotherapy for patients with T-ALL, according to the researchers. Asparaginase depletes serum asparagine by deamination into aspartic acid. While normal hematopoietic cells can survive due to ASNS activity, leukemia cells are expected to undergo apoptosis due to silencing of the ASNS gene.
ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with the poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance, the researchers stated.
“ASNS methylation status may be a clinically useful biomarker to predict sensitivity to asparaginase therapy in T-ALL patients. Considering the severe complications of asparaginase therapy particularly in adolescents and adults, stratifying prospective asparaginase therapy according to ASNS methylation status may be beneficial for safer and more effective treatment of T-ALL patients,” the researchers concluded.
The authors reported that they had no conflicts of interest.