Research Papers:

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

Salvatore Nicola Bertuccio, Salvatore Serravalle, Annalisa Astolfi, Annalisa Lonetti, Valentina Indio, Anna Leszl, Andrea Pession and Fraia Melchionda _

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Oncotarget. 2017; 8:109915-109923. https://doi.org/10.18632/oncotarget.18565

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Salvatore Nicola Bertuccio1, Salvatore Serravalle1, Annalisa Astolfi1,2, Annalisa Lonetti1, Valentina Indio2, Anna Leszl3, Andrea Pession1,2 and Fraia Melchionda1

1Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

2“Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy

3Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy

Correspondence to:

Fraia Melchionda, email: [email protected]

Keywords: acute myeloid leukemia, monosomy chromosome 7, L-Asparaginase, ASNS gene

Received: November 16, 2016     Accepted: June 02, 2017     Published: June 19, 2017


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.

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