Fusion oncoprotein condensates in pediatric cancers

St. Jude Children'S Research Hospital, Memphis TN

Investigators

Abstract

PROJECT SUMMARY - OVERALL Fusion oncoproteins (FOs), arising from gene translocations, give rise to ~17% of all cancers. Notably, FOs are commonly oncogenic drivers in pediatric cancers, including many with poor prognosis. The FusOnc Program Project synergistically assembles leading basic and translational scientists to collaboratively study FOs seen in pediatric cancers, including acute lymphoblastic and myeloid leukemias (ALL & AML, Mullighan & Klco), ependymoma (EPN, Mack) and mesenchymal chondrosarcoma (MCS, Wang). Many FOs promote oncogenesis by driving aberrant gene expression. Recently, FusOnc investigators showed that FOs deregulate gene expression by forming aberrant nuclear biomolecular condensates. Biomolecular condensates are membraneless, meso-scale assemblies that mediate diverse biological processes in healthy cells, including regulation of gene expression. FusOnc researchers have shown that several FOs form aberrant condensates that deregulate gene expression—so-called “onco-condensates”. Examples include: NUP98 and NUTM1 FOs in acute leukemia, ZFTA:RELA in ependymoma, and HEY1::NCOA2 in mesenchymal chondrosarcoma. However, despite these advances, future studies are needed to address the following questions: (1) Do FOs generally drive oncogenesis through condensate formation across the diverse landscape of pediatric cancer? and (2) Will gaining this mechanistic knowledge propel the development of novel FO-targeted therapies? The FusOnc Program Project assembles experts in condensate biophysics (Kriwacki, Project 1), MCS (Wang, Project 1), pediatric ALL and AML (Mullighan & Klco, Project 2), EPN (Mack, Project 3), biostatistics (Pounds, Core 1), CRISPR tiling-based functional analyses of FOs (Chen, Core 2) and optogenetic induction of FO condensates (Xu, Core 3) to address the questions above by accomplishing four overarching goals. Goal 1 will elucidate the biophysical mechanisms underlying condensate formation by FOs. Goal 2 will discover how FOs deregulate gene expression, alter chromatin landscapes, and promote oncogenesis. Goal 3 will identify the protein interaction partners of FOs and the underlying mechanisms of their interactions. And Goal 4 will reveal potential therapeutic targets for treatment of FO-driven pediatric cancers. These Goals will be accomplished through multiple collaborative interactions and synergies between Projects and Cores involving, the exchange of reagents, sharing of data analysis platforms, dissemination of statistical expertise, provision of several advanced technical platforms, sharing of technical expertise, and the development and sharing of cellular and in vivo cancer model systems. We strongly argue that the FusOnc Program Project will revolutionize our mechanistic understanding of several high-risk, FO-driven pediatric cancers and propel the development of mechanism-based targeted therapies against these cancers.