PhD defence M. (Milad) Rasouli

Below is a brief summary of the dissertation: 

About 3-8% of kids with acute myeloid leukemia (AML) have a genetic change called NUP98 rearrangement (NUP98r). This change depends on a protein complex, MLL-menin, to activate certain genes, much like other AML types with KMT2A or NPM1 changes. We thought a drug called Revumenib, which blocks menin, might work against NUP98r AML.
In lab tests, Revumenib strongly slowed down the growth of NUP98r AML cells, reduced their ability to form new colonies, and pushed them to mature into healthier cells. In mice with NUP98r and another mutation (FLT3-ITD), Revumenib helped them live longer.
We also noticed that NUP98r AML is similar to another tough-to-treat AML type called UBTF-TD, which has a poor outlook. Our tests showed UBTF-TD AML is also sensitive to Revumenib because of how it interacts with the KMT2A protein. We expanded our research and found that AML with DEK::NUP214 fusions or normal genetic profiles but unique gene activity also responded to Revumenib.
By studying AML samples from patients, we discovered that high levels of three genes—MEIS1, PBX3, and HOXA9-10—predict which AML types will respond well to menin-blocking drugs like Revumenib. These findings suggest that AML patients with these gene patterns should be included in clinical trials for menin inhibitors, offering hope for better treatments for these aggressive blood cancers.