Transcription Factor Activation Profiles (TFAP) identify compounds promoting differentiation of Acute Myeloid Leukemia cell lines

Abstract

Repurposing of drugs for new therapeutic use has received considerable attention for its potential to reduce time and cost of drug development. Here we present a new strategy to identify chemicals that are likely to induce differentiation of leukemic cells. As Acute Myeloid Leukemia (AML) is the result of a block in myeloid differentiation, finding new drugs that are capable of inducing blast terminal maturation is considered a valuable strategy. We used data from the Connectivity Map (CMap) to identify drugs that could be repositioned for their potential to activate transcription factors that mediate myeloid differentiation. Compounds promoting the activation of transcription factors that play a positive role in myeloid differentiation were considered candidate pro-differentiation drugs. This approach yielded a list of chemicals ranked according to the potential to activate transcription factors that induce differentiation of leukemic progenitor cells. Drugs that are already used in differentiation therapy, such as for instance all-trans retinoic acid (ATRA) are in the top positions of this ranked list. To validate our strategy, we tested the in vitro differentiation potential of 22 candidate compounds using the HL-60 human cell line as a myeloid differentiation model. Ten out of 22 compounds, ranking high in the inferred list, were confirmed to induce significant differentiation of HL-60. Some of these compounds are known to trigger the DNA damage response, thus identifying this process as a target to modulate myeloid differentiation. These results underscore the potential of our approach to accelerate the drug discovery process. The method that we have developed is highly versatile and it can be adapted to different drug repurposing projects.