Research Programs:

Menin Inhibitors in AML

Menin (MEN1) is a druggable protein within the KMT2A transcriptional complex that is essential for maintaining leukemogenic transcription in Acute Myeloid Leukemia (AML). We study how Menin inhibitors disrupt KMT2A complex function and define the mechanisms underlying clinical responses and resistance in KMT2A-rearranged and NPM1-mutant AML

KMT2A-r, NPM1c, MENIN INHIBITORS

Mechanisms of Menin Inhibitor Drug Resistance

Acquired MEN1 mutations emerged as a feature of clinical resistance to Menin inhibitors. We define the structural and functional basis of acquired MEN1 resistance mutations selected by five clinically developed Menin inhibitors, with the goal of informing next-generation inhibitor design.

MEN1 MUTATIONS, REVUMENIB, BLEXIMENIB, ZIFTOMENIB, ENZOMENIB, EMILUMENIB

Menin Inhibitor Induced Protein Degradation

Menin inhibitors induce protein stability changes within the KMT2A complex. We discovered that UBR5, a chromatin-bound E3 ubiquitin ligase, mediates inhibitor-induced destabilization of the KMT2A complex and modulates Menin inhibitor efficacy

CHROMATIN BOUND E3 LIGASES, UBR5, INHIBITOR INDUCED PROTEIN DEGRADATION 

Chromatin Biology Technology Development

We strive to further develop tools to study proteins on chromatin. By combining ion exchange fractionation methods, proximity labeling mass spectrometry-based proteomics, and chromatin capture, we aim to better assay how oncogenic complexes are assembled and maintained to sustain leukemic transcription.

ChIP, BioID, FRACTIONATION PROTEOMICS

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Funding:
National Cancer Institute (NCI)/National Institutes of Health (NIH),
Sumitomo Pharma America, Inc,
Department of Pediatrics, Oregon Health & Science University