Pediatric acute myeloid leukemia (AML) is a blood cancer with a poor prognosis. Many types of AML are driven by cut-and-paste errors called chromosomal rearrangements that join parts of two different genes to produce cancer-causing oncogenic fusion proteins. One example of an oncogenic fusion protein in AML is produced by chromosomal rearrangements involving the Nucleoporin 98 gene (NUP98-r). Children with NUP98-r AML make up the highest percentage of patients with relapsed and incurable disease. Our goal—and the mission of the Charles H. Hood Foundation Child Health Research Awards Program—is to find better, safer therapies, and to ultimately cure children with NUP98-r AML.

NUP98-fusion proteins bind to DNA, along with other proteins that have been implicated in leukemia, such as the lysine methyltransferase 2A (KMT2A) protein and its binding partner Menin. We found that treatment of NUP98-r AML with a drug that blocks the protein-protein interaction between Menin and KMT2A can halt leukemia progression and force leukemia cells to undergo differentiation, a process whereby they adopt features of a mature white blood cell and lose their cancer potential. As a result of our work, clinical trials of Menin-KMT2A inhibitors now include patients with NUP98-r AML. While our discovery may soon transform the treatment of NUP98-r AML, we recognize that combination therapy is essential for cure. The goal of this proposal is to understand whether combination therapy targeting epigenetic regulators that are essential for leukemia cell survival can improve treatment of NUP98-r AML.

Using functional genomics, we have identified chromatin complexes that regulate critical cancer promoting genes (oncogenes) that promote self-renewal and prevent differentiation of leukemia cells. Our recent work suggests that combination therapy targeting these complexes may be an effective treatment in NUP98-r AML. The results of our studies will help us understand the biologic mechanisms that drive NUP98-r leukemia, while informing better, safer therapies for children with this aggressive form of AML.