Research Projects

NUP98 fusion oncoproteins have been the primary focus of Dr. Michmerhuizen’s previous research and remain the main research interest in her lab.

NUP98 rearrangements are observed in several hematological malignancies, but occur most commonly in acute myeloid leukemia (AML) where they comprise 5% of pediatric and 3% of adult cases. NUP98 fusion oncoproteins are one of the most frequent genetic alterations in relapsed childhood AML and predict poor prognoses. NUP98 fusion oncoproteins retain the N-terminal, intrinsically disordered region of NUP98, as well as the C-terminal portion of one of over 30 fusion partners. Most partner genes include a DNA-binding or chromatin-modifying domain, which contributes to the ability of the fusion to interact with DNA and drive a stem cell-like gene expression program. Few effective therapies are available for NUP98-rearranged leukemia, and relapse occurs in nearly 70% of children with NUP98 fusion-expressing AML. These dire outcomes motivate studies to improve our mechanistic understanding of NUP98-rearranged leukemia with the goal of developing new strategies to improve patient survival.

Impact of Drug Treatment on NUP98 Fusion Condensates

Previous work from Dr. Michmerhuizen and others showed that NUP98 fusion oncoproteins localize in membrane-less organelles called condensates, which form through liquid-liquid phase separation (Ahn et al, Nature 2021; Chandra, Michmerhuizen, Shirnekhi, Tripathi et al, Cancer Discovery 2022). These condensates have a critical role in leukemic cell transformation and gene deregulation. Dr. Michmerhuizen and co-authors further characterized NUP98 fusion-associated condensates and identified their protein composition, which revealed both known and novel fusion interactors. They also demonstrated that fusion oncoprotein target genes, including HOXA/B and MEIS1, are expressed from condensates. Despite these insights and the importance of condensates for leukemic phenotypes, little is known about the impact of drug treatment on condensate integrity and composition. This project aims to determine how effective small molecule inhibitors alter the features of fusion-associated condensates (such as condensate volume, density, and number) as well as the functional output of these condensates (e.g., gene expression and/or histone modifications). This work is important because it will help establish whether condensate disruption or other changes are a prerequisite for the death and/or differentiation of NUP98-rearranged cells.

Targeting the NUP98 Fusion Oncoprotein Interactome

Previous studies by Dr. Michmerhuizen and others have demonstrated that NUP98 fusion oncoproteins interact with proteins involved in ribosome biogenesis, RNA splicing, and chromatin remodeling. Among these interactors are members of MYST family histone acetyltransferase complexes (KAT6A/MOZ and KAT7/HBO1). Genetic or pharmacologic targeting of KAT6A/7 led to decreased cell fitness in multiple mouse and human models of NUP98-rearranged leukemia. Moreover, treating NUP98 fusion-bearing patient derived xenografts with KAT6A/7 inhibitor PF9363 led to myeloid differentiation, reduced leukemia burden, and synergism with Menin inhibition (Michmerhuizen et al, Cancer Discovery 2025). These findings nominate KAT6A/7 inhibition as a promising treatment strategy in NUP98-rearranged leukemia and motivate additional studies to investigate therapeutic targeting of other NUP98 fusion oncoprotein interactors. This project aims to identify other critical, targetable NUP98 fusion interactors and understand how they contribute to leukemia development and/or progression. Ultimately, this work seeks to nominate new treatment strategies for patients with NUP98-rearranged leukemia and consider how they can be used most effectively as single agents or in combination with other promising therapies.

Extending These Ideas to Other Fusion Oncoproteins

Many other fusion oncoproteins also localize in condensates, but the implications of this are not well-studied. Research in the Michmerhuizen lab is actively expanding to explore other fusion oncoproteins in childhood leukemia (such as PAX5 fusions, CBFA2T3::GLIS2) and in other cancer types.