Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

Barry M. Zee, Kamrine E. Poels, Cong Hui Yao, Kimihito C. Kawabata, Gongwei Wu, Cihangir Duy, William D. Jacobus, Elizabeth Senior, Jennifer E. Endress, Ashwini Jambhekar, Scott B. Lovitch, Jiexian Ma, Abhinav Dhall, Isaac S. Harris, M. Andres Blanco, David B. Sykes, Jonathan D. Licht, David M. Weinstock, Ari Melnick, Marcia C. HaigisFranziska Michor, Yang Shi

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Article number102651
JournaliScience
Volume24
Issue number6
DOIs
StatePublished - 25 Jun 2021
Externally publishedYes

Keywords

  • molecular biology
  • stem cell research
  • systems biology

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