Ebelt Nancy D, Loganathan Suvithanandhini, Avsharian Lara C, Manuel Edwin R
Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA.
bioRxiv. 2024 Dec 5:2024.12.01.626276. doi: 10.1101/2024.12.01.626276.
Hypomethylating agents (HMAs), such as decitabine and 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia that are ineligible for intensive chemotherapy. Despite providing significant extensions in survival when used alone or in combination, eventual relapse and resistance to HMAs are observed. The mechanisms leading to these outcomes are still not well defined and may, in part, be due to a focus on leukemic populations with limited information on the effects of HMAs on non-leukemic cells in the blood and other tissue compartments. In this study, we elucidated effects on immune-related gene expression in non-leukemic blood cells and the spleen during AZA treatment in leukemia-challenged mice. We observed significant changes in pathways regulating adhesion, thrombosis, and angiogenesis as well as a dichotomy in extramedullary disease sites that manifests during relapse. We also identify several genes that may contribute to the anti-leukemic activity of AZA in blood and spleen. Overall, this work has identified novel gene targets and pathways that could be further modulated to augment efficacy of HMA treatment.
去甲基化药物（HMAs），如地西他滨和5-氮杂胞苷（AZA），是不适用于强化化疗的急性髓系白血病患者的重要治疗选择。尽管单独使用或联合使用时能显著延长生存期，但最终仍会出现复发和对HMAs耐药的情况。导致这些结果的机制仍未明确，部分原因可能是研究主要集中在白血病细胞群体，而对血液和其他组织区室中的非白血病细胞受HMAs影响的信息了解有限。在本研究中，我们阐明了在白血病模型小鼠接受AZA治疗期间，其对非白血病血细胞和脾脏中免疫相关基因表达的影响。我们观察到调节黏附、血栓形成和血管生成的信号通路发生了显著变化，以及复发期间出现的髓外疾病部位的二分法。我们还鉴定了几个可能有助于AZA在血液和脾脏中发挥抗白血病活性的基因。总体而言，这项工作确定了新的基因靶点和信号通路，可进一步调控以增强HMA治疗的疗效。
