Differential mechanisms of asparaginase resistance in B-type acute lymphoblastic leukemia and malignant natural killer cell lines

Abstract

Bacterial L-asparaginase (ASNase), hydrolyzing L-asparagine (Asn), is an important drug for treating patients with acute lymphoblastic leukaemia (ALL) and natural killer (NK) cell lymphoma. Although different native or pegylated ASNase-based chemotherapy are efficient, disease relapse is frequently observed, especially in adult patients. The neo-synthesis of Asn by asparagine synthetase (AsnS) following ASNase treatment, which involves the amino acid response and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways, is believed to be the basis of ASNase-resistance mechanisms. However, AsnS expression has not emerged as an accurate predictive factor for ASNase susceptibility. The aim of this study was to identify possible ASNase sensitivity/resistance-related genes or pathways using a new asparaginase, namely a pegylated r-crisantaspase, with a focus on classic Asn-compensatory responses and cell death under conditions of Asn/L-glutamine limitation. We show that, for B-ALL cell lines, changes in the expression of apoptosis-regulatory genes (especially NFκB-related genes) are associated with ASNase susceptibility. The response of malignant NK cell lines to ASNase may depend on Asn-compensatory mechanisms and other cellular processes such as cleavage of BCL2A1, a prosurvival member of the Bcl-2 protein family. These results suggest that according to cellular context, factors other than AsnS can influence ASNase susceptibility.

Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo

“…Indeed, different formulations of L-asparaginase have been an integral part of the treatment for acute lymphoblastic leukemia for many years [22]. Resistance to L-asparaginase treatment is often accompanied by up-regulation of ASNS [10, 11, 23, 24]. Therefore, means to inhibit ASNS enzyme activity or synthesis are considered to be helpful to counteract evolving resistance.…”

“…Nevertheless, there is growing evidence that this view is too simplistic [11] and recent research shows that L-asparaginase might be useful for the treatment of solid malignancies as well [12]. In our study, we focused on glioblastoma WHO IV, which is the most common primary brain tumor in adults and bears a grim prognosis with median survival rates of less than 1.5 years [13].…”

Differentiating hypersensitivity versus infusion-related reactions in pediatric patients receiving intravenous asparaginase therapy for acute lymphoblastic leukemia

“…[10] Asparaginase depletes serum levels of asparagine, effectively depriving leukemia cells of this critical amino acid. [10] Although the relationship between asparagine-synthetase expression and outcomes remains controversial, [11][12][13] it has been shown that continuous and prolonged asparagine depletion is associated with improved outcomes. [6] In a study of 377 pediatric patients treated on a Dana-Farber Cancer Institute (DFCI) protocol, investigators found superior outcomes for patients who completed !26 consecutive weeks of asparaginase treatment compared with patients who received <26 weeks (90 ± 2% vs. 73 ± 7%; p < .01).…”

A clinically attainable dose of L‐asparaginase targets glutamine addiction in lymphoid cell lines

“…Taken together, these reports and our findings suggest that GLS could be a biomarker of Gln dependence and a therapeutic target. In contrast, another report stated that changes in the expression of apoptosis‐regulatory genes (especially NF‐κB‐related genes) are associated with L‐ASNase susceptibility in B‐ALL cell lines . These findings therefore suggest that multiple factors other than Asn‐dependency and ASNS, including GLS1, can influence L‐ASNase action and susceptibility depending on the cellular context .…”

“…In contrast, another report stated that changes in the expression of apoptosis‐regulatory genes (especially NF‐κB‐related genes) are associated with L‐ASNase susceptibility in B‐ALL cell lines . These findings therefore suggest that multiple factors other than Asn‐dependency and ASNS, including GLS1, can influence L‐ASNase action and susceptibility depending on the cellular context . Future studies using clinical samples may provide insights for the precise mechanisms of L‐ASNase in ALL and malignant lymphoma.…”