Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia
| العنوان: | Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia |
|---|---|
| المؤلفون: | David M. Weinstock, Kamrine E. Poels, Franziska Michor, Abhinav Dhall, Cong-Hui Yao, Isaac S. Harris, Gongwei Wu, Marcia C. Haigis, Elizabeth Senior, Scott B. Lovitch, Jiexian Ma, Barry M. Zee, M Andres Blanco, Kimihito Cojin Kawabata, Ari Melnick, David B. Sykes, William D. Jacobus, Jonathan D. Licht, Cihangir Duy, Jennifer E. Endress, Yang Shi, Ashwini Jambhekar |
| المصدر: | iScience, Vol 24, Iss 6, Pp 102651-(2021) iScience |
| بيانات النشر: | Cell Press, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Purine nucleotide salvage, stem cell research, Myeloid, Science, 02 engineering and technology, Article, 03 medical and health sciences, hemic and lymphatic diseases, medicine, molecular biology, Epigenetics, Transcription factor, Multidisciplinary, biology, Myeloid leukemia, systems biology, 021001 nanoscience & nanotechnology, Chromatin, 030104 developmental biology, medicine.anatomical_structure, Histone, biology.protein, Cancer research, Demethylase, 0210 nano-technology |
| الوصف: | Summary A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML. Graphical abstract Highlights • Combined epigenetic and metabolic perturbations induce myeloid differentiation • Combination treatment alters nucleotide, lipid, and gene expression profiles • Combination treatment induces differentiation of human acute myeloid leukemia cells Molecular biology; Stem cells research; Systems biology |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e0c97b808af14a9cdec8dafb955a48b https://ora.ox.ac.uk/objects/uuid:cf69f19c-948e-46e0-b31e-52a62f5e863f |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6e0c97b808af14a9cdec8dafb955a48b |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |