Combination of menin and kinase inhibitors as a novel treatment for NUP98-rearranged leukemia
Chromosomal translocations involving the nucleoporin 98 (NUP98) gene at chromosome 11p15 are found in pediatric and adult Acute Myeloid Leukemia (AML) patients, representing one of the most common genetic alterations in pediatric AMLs found in ~10% of these patients. Previous studies demonstrated that NUP98 fusion proteins interact with MLL1 (Mixed Lineage Leukemia 1 also known as KMT2A) protein complex, and colocalize with MLL1 on Hoxa/b cluster genes, supporting MLL1 as a molecular dependency in the NUP98-r leukemia. Importantly, recent work has validated an important role of the scaffold protein menin, which directly interacts with the N-terminus of MLL1, in the NUP98-r leukemia. Here, we explored the effect of combining our menin inhibitor MI-3454 with CDK6 or FLT3 kinase inhibitors in the NUP98-r leukemia models as a possible way to enhance the anti-leukemic effect. Overall design: This project explored the effects of combining MENIN inhibition with kinase inhibitors on the growth and gene expression of acute myeloid leukemia cells. Primary AML patient samples with NUP98 translocations were obtained from 1) adult bone marrow harboring a NUP98-HOXA9 mutation or 2) pediatric bone marrow harboring NUP98-NSD1 mutation. The adult AML primary sample was treated with MI3454 (MENIN inhibitor), Gilteritinib (FLT3 kinase inhibitor), Palbociclib (CDK4/6 kinase inhibitor), or combinations of MI3454 with each of the kinase inhibitors (in triplicate for each treatment group). The pediatric primary AML sample was amplified in vivo by transplantation to mice, then cells were harvested and treated with MI3454, Palbociclib, or a combination of the two (in triplicate for each treatment group). Differential gene expression for each single agent treatment or combination compared to vehicle controls were then calculated and compared across treatments and patient samples.