Dynamic, anthracycline-induced chromatin alterations enable ALDH1 expression as a mechanism of inducible leukemia resistance development.

The evolution of acute myeloid leukemia (AML) cells toward developing drug resistance, which eventually leads to relapse, involves the convergence of their chromatin compaction status toward a pattern that is distinctive of "stem-like" cells and is conducive to increased expression of nuclear factor kappa B (NFκB). This phenomenon develops irrespective of the genetic mutations carried by the AML clones. Multiple lines of evidence therefore suggest that relapsed and refractory leukemia develops through alterations in chromatin, which perturb the normal cellular regulation of inflammatory and stress responses. In particular, during the development of acute leukemia phenotypes that resist drug treatment and give rise to relapse, malignant clones carrying different genetic alterations often converge into specific phenotypes with the apparent criterion being shared patterns of chromatin exposure. These shared patterns include genes involved in innate immune pathways that provide malignant cells with a selective advantage. Such a selective advantage is provided also by expression of cytosolic retinaldehyde dehydrogenases such as ALDH1A1, which was shown to characterize AML cells driving relapse, and which are resistant to chemotherapy.