Cathepsin B Is Not an Intrinsic Factor Related to Asparaginase Resistance of the Acute Lymphoblastic Leukemia REH Cell Line.
Cathepsin B Is Not an Intrinsic Factor Related to Asparaginase Resistance of the Acute Lymphoblastic Leukemia REH Cell Line.
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DOI：
10.3390/ijms241311215
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发表时间：
2023-07-07
影响因子：
5.6
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中科院分区：
文献类型：
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L-天冬酰胺酶（ASNase）是一种用于治疗急性淋巴细胞白血病（ALL）的基本药物。然而，一些ALL病例对ASNase治疗天然耐药，导致预后不良。REH ALL细胞系用作研究最常见的ALL亚型的模型，被认为对ASNase治疗具有抗性。组织蛋白酶B（CTSB）是参与调节体内ASNase血清半衰期的蛋白酶之一，并且其还与几种实体瘤的进展和对治疗的抗性相关。以前的工作已经表明，在体外，ASNase被降解时，与REH细胞裂解物，这是由一个特定的CTSB抑制剂阻止孵育，这表明该蛋白酶的功能，在ASNase抗性的REH细胞。在这项工作中，我们利用CRISPR/Cas9基因靶向和酶促测量的组合来研究CTSB对ALL模型细胞系中ASNase治疗抗性的相关性。我们发现，REH ALL细胞中CTSB的缺失并不赋予ASNase治疗敏感性，因此表明CTSB的内在表达不是驱动这些ALL细胞对用作白血病一线治疗的酶的抗性性质的机制。
L-Asparaginase (ASNase) is a biopharmaceutical used as an essential drug in the treatment of acute lymphoblastic leukemia (ALL). Yet, some cases of ALL are naturally resistant to ASNase treatment, which results in poor prognosis. The REH ALL cell line, used as a model for studying the most common subtype of ALL, is considered resistant to treatment with ASNase. Cathepsin B (CTSB) is one of the proteases involved in the regulation of in vivo ASNase serum half-life and it has also been associated with the progression and resistance to treatment of several solid tumors. Previous works have shown that, in vitro, ASNase is degraded when incubated with REH cell lysate, which is prevented by a specific CTSB inhibitor, suggesting a function of this protease in the ASNase resistance of REH cells. In this work, we utilized a combination of CRISPR/Cas9 gene targeting and enzymatic measurements to investigate the relevance of CTSB on ASNase treatment resistance in the ALL model cell line. We found that deletion of CTSB in REH ALL cells did not confer ASNase treatment sensitivity, thus suggesting that intrinsic expression of CTSB is not a mechanism that drives the resistant nature of these ALL cells to enzymes used as the first-line treatment against leukemia.
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