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

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.
Competing Interests: Y.S. is a co-founder and equity holder of Constellation Pharmaceuticals, Athelas Therapeutics and K36 Therapeutics, a consultant for Active Motif, and an equity holder of Imago Biosciences. I.S.H. is a consultant for ONO Pharma USA. D.B.S. is a co-founder and an equity holder of Clear Creek Bio. Y.S., B.M.Z, J.M., and A.D. are developers of the LSD1 inhibitor combinations described in this report and Boston Children's Hospital has pursued a patent application of this technology. All other authors declare no competing financial interests.
(© 2021 The Author(s).)