Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase

Abstract

L-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients.

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

“…ASNS expression is regarded as an important biomarker for therapeutic outcome in cancers. Hematological malignancies with ASNS deletions respond favorably to L‐asparaginase chemotherapeutics and rarely relapse (Bertuccio et al, ), whereas its low expression in colon carcinoma of patients undergoing chemoradiotherapy is associated with poor survival and inferior chemotherapeutic response (Lin et al, ). In our study, ASNS did not correlate with the clinical outcome of our patients; however, there is scope to examine its role in the management of the ocular tumor or its secondaries.…”

Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia

“…When added to high-dose cytarabine, asparaginase significantly increased complete remission rates and overall survival in adult patients with R/R AML when compared to high-dose cytarabine alone [7]. Additionally, asparaginase has been shown to have particularly high activity in AML when cell lines have a deletion of chromosome 7 [8]. Chromosome 7 is responsible for the production of asparagine synthetase, and its depletion (through a deletion of chromosome 7) results in the leukemic cell's inability to overcome the activity of asparaginase.…”

Model guided trait-specific co-expression network estimation as a new perspective for identifying molecular interactions and pathways

“…done based on the interaction term between ASNS and GAB2, median survival times were 26 months in the low-risk group (high expression) and 12 months in the high-risk (low expression) group using the TCGA dataset. However, it has been shown in [45] that high ASNS expression values reduce survival times. In light of this example, it appears that we should be careful with such a conclusion.…”