Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine.
Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine.
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DOI：
10.1158/0008-5472.can-12-4402
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Mittelman SD
中科院分区：
文献类型：
--
作者：
Ehsanipour EA;Sheng X;Behan JW;Wang X;Butturini A;Avramis VI;Mittelman SD
肥胖是癌症的一个重要风险因素。肥胖与一种儿童癌症之间的关联已被确定：被诊断患有高危急性淋巴细胞白血病（ALL）的肥胖儿童复发风险比消瘦儿童高50%。L - 天冬酰胺酶（ASNase）是治疗ALL的一线疗法，它分解天冬酰胺和谷氨酰胺，利用了ALL细胞比其他细胞更依赖这些氨基酸这一事实。在本研究中，我们探究了产生大量谷氨酰胺的脂肪细胞是否可能抵消ASNase的作用。在接受高危ALL治疗的儿童中，肥胖与天冬酰胺或谷氨酰胺的血浆水平改变无关。然而，诱导化疗后骨髓脂肪细胞中的谷氨酰胺合成酶显著增加。在移植了同基因ALL细胞的小鼠中，肥胖极大地削弱了ASNase的疗效，并且和在人类中一样，不影响血浆天冬酰胺或谷氨酰胺水平。在共培养中，脂肪细胞抑制了ASNase诱导的白血病细胞毒性，并且这种保护作用依赖于谷氨酰胺的分泌。这些发现表明，脂肪细胞与白血病微环境中的其他细胞协同作用，在ASNase治疗期间保护白血病细胞。
Obesity is a significant risk factor for cancer. A link between obesity and a childhood cancer has been identified: obese children diagnosed with high-risk acute lymphoblastic leukemia (ALL) had a 50% greater risk of relapse than their lean counterparts. L-asparaginase (ASNase) is a first-line therapy for ALL that breaks down asparagine and glutamine, exploiting the fact that ALL cells are more dependent on these amino acids than other cells. In the present study, we investigated whether adipocytes, which produce significant quantities of glutamine, may counteract the effects of ASNase. In children being treated for high-risk ALL, obesity was not associated with altered plasma levels of asparagine or glutamine. However, glutamine synthetase was markedly increased in bone marrow adipocytes after induction chemotherapy. Obesity substantially impaired ASNase efficacy in mice transplanted with syngeneic ALL cells, and, like in humans, without affecting plasma asparagine or glutamine levels. In co-culture, adipocytes inhibited leukemic cell cytotoxicity induced by ASNase, and this protection was dependent on glutamine secretion. These findings suggest that adipocytes work in conjunction with other cells of the leukemia microenvironment to protect leukemia cells during ASNase treatment.