Highlighted Publications
We demonstrated that the Menin-MLL1/KMT2A interaction is a therapeutically actionable, molecular dependency in Nucleoporin 98 (NUP98)-rearranged acute myeloid leukemia (AML). This paper provided the first preclinical evidence that small molecule inhibitors of the Menin-KMT2A protein-protein interaction may be effective in this aggressive form of AML. As a result of our publication, patients with NUP98-rearranged AML are now included in ongoing trials of Menin inhibitors.
We determined the mechanism by which key oncogenes are silenced upon removal of the NUP98-fusion protein from chromatin. Here, we identify the non-canonical polycomb repressive complex 1.1 (PRC1.1) as an essential component of the epigenetic machinery that is required for repression of pro-leukemogenic gene expression. We use complementary methods to displace or degrade the NUP98-fusion protein to demonstrate a requirement for polycomb-mediated histone modifications and transcriptional silencing in NUP98-rearranged leukemia. These results suggest that patients whose leukemia harbors loss-of-function mutations in PRC1.1 components such as BCOR/BCORL1 may be resistant to Menin inhibitors.
In this Cancer Discovery paper, we and our collaborators in the Mullighan Lab at St. Jude identify the MYST family histone acetyltransferases KAT6A and KAT7 as novel molecular dependencies in NUP98-rearranged leukemia. Small molecule inhibitors of KAT6A/7 enzymatic activity halt leukemogenesis, induce myeloid differentiation, and overcome Menin inhibitor resistance in NUP98-rearranged patient-derived xenograft leukemia models in vivo.
Read about our perspective on the Phase I/II clinical trial of Revumenib in KMT2A-rearranged leukemia in an 'Understanding the Pathway' article, commenting on https://ascopubs.org/doi/10.1200/JCO.24.00826
