PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

• Published in: Nature communications Vol. 15; no. 1; pp. 9697 - 19
• Main Authors: Beck, Dominik, Cao, Honghui, Tian, Feng, Huang, Yizhou, Jiang, Miao, Zhao, Han, Tai, Xiaolu, Xu, Wenqian, Kosasih, Hansen J., Kealy, David J., Zhao, Weiye, Taylor, Samuel J., Couttas, Timothy A., Song, Gaoxian, Chacon-Fajardo, Diego, Walia, Yashna, Wang, Meng, Dowle, Adam A., Holding, Andrew N., Bridge, Katherine S., Zhang, Chao, Wang, Jin, Mi, Jian-Qing, Lock, Richard B., de Bock, Charles E., Jing, Duohui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45/15; 45/23; 45/43; 45/91; 49/23; 49/39; 64/60; 692/4017; 692/4028/67/1990/283/2125; 692/4028/67/69; 82/58; 96/31; Acute lymphoblastic leukemia; Animals; Apoptosis; Apoptosis - drug effects; Cancer; Cell Line, Tumor; Chromatin; Chromatin - metabolism; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic - drug effects; Epigenetics; Female; Gene Expression Regulation, Leukemic - drug effects; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - pharmacology; Humanities and Social Sciences; Humans; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Mice; multidisciplinary; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; PU.1 protein; Receptors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Regulatory mechanisms (biology); Regulatory sequences; Resistance factors; Response Elements; Science; Science (multidisciplinary); Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Xenograft Model Antitumor Assays; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54096-2

The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance. Glucocorticoid resistance is partly due to epigenetic alterations, but the regulatory mechanisms driving these remain poorly understood. Here, a link between the activity of a lineage-specific transcription factor PU.1 and epigenetic modulators mediating the response to glucocorticoids is described in acute lymphoblastic leukemia.