RNA expression data suggest ALDH2 inhibition as a concept for killing acute myeloid leukemia cells that are resistant to ALDH1 inhibitors: the example of NPM1 mutant AML

Abstract

In this data paper we present a study of RNA expression in association with the disease course of acute myeloid leukemia (AML). We have previously identified aldehyde dehydrogenase genes ALDH1A1 and ALDH2 as prospective actionable targets in AML. ALDH1A1 is expected to have key functions in leukemia stem-like cells that are prone to a dormant state in terms of metabolic activity and proliferation. Cells with a higher activity of metabolism as a whole and in mitochondria in particular, are likely to generate a higher abundance of formaldehyde and acetaldehyde. Cell survival necessitates removal of formaldehyde and acetaldehyde, which is to a substantial degree the function of ALDH2. AML cells with a mutant NPM1 gene permit higher MYC activity which would lead to increased metabolic activity. Extended MYC activity is allowed by the mutant NPM1 protein, compared to NPM1 wild-type. Here, we show that survival analysis in patients with NPM1 mutant AML yields a higher hazard ratio for ALDH2 RNA than for ALDH1A1, which is not the case for patients with wild-type NPM1. This result is consistent with the difference in enzymatic function between ALDH2 and ALDH1A1, the latter of which is not suited for small aldehydes, especially formaldehyde. This should open the door to the examination of ALDH2 inhibitors such as the clinically approved disulfiram, for the treatment of NPM1 mutant AML that proves refractory to ALDH1A1 inhibition.