Cerebrospinal fluid attenuates the efficacy of methotrexate against acute lymphoblastic leukemia cells

Blood Neoplasia Pub Date : 2025-02-01 DOI:10.1016/j.bneo.2024.100057

Jongseok Kang ∗ , Jason Ostergaard ∗ , Xiaohong Wang , Peter M. Gordon

{"title":"Cerebrospinal fluid attenuates the efficacy of methotrexate against acute lymphoblastic leukemia cells","authors":"Jongseok Kang ∗ , Jason Ostergaard ∗ , Xiaohong Wang , Peter M. Gordon","doi":"10.1016/j.bneo.2024.100057","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>Treatment and prophylaxis of the central nervous system (CNS) is a standard component of acute lymphoblastic leukemia (ALL) therapy. However, CNS-directed therapies are a significant cause of morbidity, and CNS relapse remains a cause of treatment failure. CNS-directed ALL therapies must target leukemia cells within cerebrospinal fluid (CSF), a fluid that is compositionally distinct from plasma and has been shown to affect leukemia biology. Herein, we demonstrate that human CSF attenuates the potency and efficacy of antifolate drugs including methotrexate, the primary CNS-directed chemotherapeutic for >6 decades. Importantly, this effect of CSF on leukemia methotrexate sensitivity was reversible. Additional mechanistic studies support that diminished proliferation and activation of the integrated stress response in leukemia cells in the CSF may contribute to this resistance. Our findings suggest potential strategies to enhance methotrexate efficacy in CNS-directed ALL therapy and highlight the need to critically reassess even established standards of care.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100057"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328024000578","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

Abstract

Treatment and prophylaxis of the central nervous system (CNS) is a standard component of acute lymphoblastic leukemia (ALL) therapy. However, CNS-directed therapies are a significant cause of morbidity, and CNS relapse remains a cause of treatment failure. CNS-directed ALL therapies must target leukemia cells within cerebrospinal fluid (CSF), a fluid that is compositionally distinct from plasma and has been shown to affect leukemia biology. Herein, we demonstrate that human CSF attenuates the potency and efficacy of antifolate drugs including methotrexate, the primary CNS-directed chemotherapeutic for >6 decades. Importantly, this effect of CSF on leukemia methotrexate sensitivity was reversible. Additional mechanistic studies support that diminished proliferation and activation of the integrated stress response in leukemia cells in the CSF may contribute to this resistance. Our findings suggest potential strategies to enhance methotrexate efficacy in CNS-directed ALL therapy and highlight the need to critically reassess even established standards of care.

查看原文本刊更多论文

脑脊液减弱甲氨蝶呤对急性淋巴细胞白血病细胞的疗效

摘要中枢神经系统（CNS）的治疗和预防是急性淋巴细胞白血病（ALL）治疗的标准组成部分。然而，中枢神经系统定向治疗是发病率的重要原因，中枢神经系统复发仍然是治疗失败的原因。中枢神经系统导向的ALL治疗必须靶向脑脊液（CSF）中的白血病细胞，脑脊液是一种成分不同于血浆的液体，已被证明会影响白血病生物学。在此，我们证明了人类脑脊液减弱了抗叶酸药物的效力和疗效，包括60年来主要的中枢神经系统定向化疗药物甲氨蝶呤。重要的是，CSF对白血病甲氨蝶呤敏感性的影响是可逆的。另外的机制研究支持脑脊液中白血病细胞增殖减少和综合应激反应的激活可能有助于这种抵抗。我们的研究结果提示了提高甲氨蝶呤在中枢神经系统指导的ALL治疗中的疗效的潜在策略，并强调了对已建立的治疗标准进行批判性重新评估的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Blood Neoplasia

自引率

0.00%

发文量