Identification and characterization of aneuploidy-selective compounds in acute myeloid leukemia

Abstract

Aneuploidy is a rare condition in untransformed cells and one of the hallmarks of cancer. It often coexists with chromosomal instability and correlates with intra-tumor heterogeneity and poor clinical outcome. Several studies performed in various organisms engineered to harbor chromosome abnormalities have revealed that aneuploidy confers common phenotypes such as intracellular pathway deregulation and increased energy and metabolic requests, all eventually impairing cellular fitness. Even if the majority of aneuploid cells are less proliferatively active than normal diploid cells, favorable karyotypic variants and selection pressure can confer a growth advantage to chromosomally unstable cells, due to their improved adaptability, possibly promoting tumorigenesis. As a rare event in normal tissues, aneuploidy constitutes an attractive potential therapeutic target for cancer treatment. Indeed, some studies have started to investigate this opportunity, mainly in cell line models, leading to the identification of some compounds that specifically target aneuploidy. Acute myeloid leukemia (AML) patients with aneuploid karyotypes respond poorly to conventional chemotherapy. Thus, the identification of aneuploidy-specific antiproliferative compounds that could be used for the treatment of this subset of AML patients constitutes an intriguing strategy. Here we show that 8-azagunanine is a potential aneuploidy-selective antiproliferative compound in AML. 8-Azaguanine causes endoplasmic reticulum stress, possibly exacerbating proteotoxic stress as one of the predominant features of aneuploid cells, and specifically enhances the death of cells with abnormal karyotypes. Moreover, we demonstrate in AML cells that p53 deficiency enables the propagation of extensive karyotypic heterogeneity and chromosome abnormalities including structural aneuploidy (gains or losses of sub-chromosomal regions) and structural rearrangements (alterations of chromosome structure), which are conversely prevented in p53-proficient cells. Numerical aneuploidy, on the other hand, does not inevitably trigger p53 activation. These results suggest that p53 provides maintenance of genomic stability especially with regard to structural chromosome abnormalities.