Cerebrospinal fluid attenuates the efficacy of methotrexate against acute lymphoblastic leukemia cells
Year: 2024
Type: article
Abstract: • CSF reversibly attenuates the efficacy of antifolate drugs, including methotrexate, against leukemia cells. • Reduced proliferation and integrated stress response activation in leukemia cells in CSF may contribute to this resistance. 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.
Source: Blood Neoplasia
Institutions: University of Minnesota, Masonic Cancer Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
OpenAlex ID: W4404429654