The phenotypical differences arising from minor variations at the molecular level could have major effect on responses of leukemias to drugs. To address this issue we are screening the in vitro biological responses of primary human acute myeloid leukemia (AML) cells to various collections of chemical compounds in a media that transiently inhibits differentiation and supports leukemia stem cell activity ex vivo.

Combination of biological responses to compounds with clinical, molecular and genetic data show that:

  • cellular responses to some compounds correlate with clinical outcome
  • some clinically approved drugs selectively inhibit only a fraction of specimens
  • AML subgroups sharing a mutated pathway exhibit a distinct subgroup-specific compound responses
  • interspecimen response variations identify compound clusters suggesting existence of a previously not identified shared pathway

In addition to improving prognostic stratification of AML our chemogenomic approach enables identification of novel compounds that selectively kill AML cell and identification of pathways that might represent novel therapeutic targets (Baccelli et al., Blood Cancer, 2017).