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Zee BM , Poels KE , Yao CH , Kawabata KC , Wu G , Duy C , Jacobus WD , Senior E , Endress JE , Jambhekar A , Lovitch SB , Ma J , Dhall A , Harris IS , Blanco MA , Sykes DB , Licht JD , Weinstock DM , Melnick A , Haigis MC , Michor F , Shi Y
Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia
iScience. 2021 Jun 25;24(6) :102651
PMID: 34151238 PMCID: PMC8192696 URL: https://www.ncbi.nlm.nih.gov/pubmed/34151238
AbstractA 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.
Notes2589-0042 Zee, Barry M Poels, Kamrine E Yao, Cong-Hui Kawabata, Kimihito C Wu, Gongwei Duy, Cihangir Jacobus, William D Senior, Elizabeth Endress, Jennifer E Jambhekar, Ashwini Lovitch, Scott B Ma, Jiexian Dhall, Abhinav Harris, Isaac S Blanco, M Andres Sykes, David B Licht, Jonathan D Weinstock, David M Melnick, Ari Haigis, Marcia C Michor, Franziska Shi, Yang Journal Article iScience. 2021 May 25;24(6):102651. doi: 10.1016/j.isci.2021.102651. eCollection 2021 Jun 25.