PROJECT SUMMARY

There are currently no treatments for MDS or AML with mutations in TP53 and complex karyotype, or MDS-CK. This type of MDS is characterized by abnormal chromosome complement, called aneuploidy.

We propose a simple but surprising idea that all aneuploid cells use shared molecular pathways to cope with the stress of having abnormal chromosomes. We aim to eradicate aneuploid cells in MDS-CK by targeting these conserved molecular pathways.

We propose a combination of two approved anti-leukemic drugs to achieve this effect, but need to learn more to about these pathways to develop better treatments. We implicate genes called cohesins in this process. Cohesins are often mutated in MDS, but almost never in MDS-CK. We want to understand how cohesins help MDS cells cope with abnormal chromosomes.

By uncovering and targeting the conserved molecular pathways that MDS cells use to cope with abnormal chromosomes, we can develop treatments that selectively eradicate malignant aneuploid stem cells with TP53 mutations in complex karyotype MDS.