NUP98 fusion oncogenes (e.g., NUP98-HOXA9, -KDM5A, and -NSD1) are associated with several hematological malignancies, including pediatric acute myeloid leukemia (AML), characterized by dismal treatment outcomes. The N-terminal FG-repeat domain that is common to all NUP98 fusion oncogenes (termed NUP98-N) is known to be intrinsically disordered and, by itself, to undergo phase separation to form gel-like bodies in vitro and large, spherical puncta in the nuclei of cells. However, these large puncta are not associated with hematopoietic cell transformation and leukemogenesis. Importantly, NUP98 fusion oncoproteins (FOs)?in which NUP98-N is fused to a variety of different C-terminal chromatin targeting domains?form many chromatin-associated, sub-micron-sized puncta that are associated with aberrant gene transcription, hematopoietic cell transformation and leukemogenesis. Recently, Young, et al., Tjian, et al., and Rivera, et al., demonstrated that critical transcriptional regulators, i) exhibit disordered regions that undergo phase separation in vitro and ii) are found within small, liquid-like puncta in cells that are proposed to form through phase separation. These dynamic puncta are proposed to drive co-localization of distal chromatin sites and organize the transcriptional machinery for coordinated expression of multiple genes. In the proposed studies, we will test the hypothesis that phase separation is a unifying mechanism that drives the formation of aberrant transcription centers by NUP98 FOs at chromatin sites targeted by their various C-terminal fused domains. These aberrant transcription centers, we propose, recruit components of the transcriptional machinery to activate expression of HOX and other genes and transform hematopoietic cells. 1

Public Health Relevance

Project 3/Narrative NUP98, which encodes a nuclear pore complex (NPC) protein, is fused to domains of various gene regulatory proteins (e.g., HOXA9, KDM5A, NSD1, PHF23) in hematological malignancies [e.g., acute myeloid leukemia (AML) & acute erythroid leukemia (AEL)] which are characterized by poor prognosis and dismal treatment outcomes. The resulting NUP98 fusion oncoproteins (FOs) have been shown to localize to small nuclear puncta that are hypothesized here to mediate aberrant gene expression associated with leukemogenesis. However, the mechanism(s) underlying the assembly and aberrant function of NUP98 FOs within nuclear puncta are not understood, limiting development of therapeutics against these poor prognosis leukemias; the proposed studies seek to address this knowledge gap. 1

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
3U54CA243124-01S2
Application #
10230529
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jhappan, Chamelli
Project Start
2019-09-19
Project End
2024-08-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105