Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents.

Cancer-directed drugs are often clinically deployed without definitive understanding of their molecular mechanisms of action (MOA). Hypomethylating agents (HMAs), which result in the degradation of the DNA methyltransferase 1 (DNMT1), have been deployed for decades in the treatment of haematological malignancies. The precise mechanism of action of these drugs, however, has been debated, rendering the design of rational combination therapies challenging.

Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.

Riboflavin is a diet-derived vitamin in higher organisms that serves as a precursor for flavin mononucleotide and flavin adenine dinucleotide, key cofactors that participate in oxidoreductase reactions. Here, using proteomic, metabolomic and functional genomics approaches, we describe a specific riboflavin dependency in acute myeloid leukemia and demonstrate that, in addition to energy production via oxidative phosphorylation, a key biological role of riboflavin is to enable nucleotide biosynthesis and iron-sulfur cluster metabolism. Genetic perturbation of riboflavin metabolism pathways or exogenous depletion in physiological culture medium induce nucleotide imbalance and DNA damage responses, as well as impair the stability and activity of proteins which utilize [4Fe-4S] iron-sulfur clusters as cofactors.

Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.

Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML.