Targeting Oncoprotein-snoRNA interaction in acute myeloid leukemia

• Applicant: Fengbiao Zhou, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576311522

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a five-year survival rate of less than 30%. In approximately 35% of AML cases, somatic mutations in the Nucleophosmin 1 (NPM1) gene result in aberrant cytoplasmic localization of the protein (NPM1c). Under physiological conditions, NPM1 is primarily localized to the nucleolus and acts as a multifunctional "hub" protein with essential roles in ribosome biogenesis, centrosome duplication, DNA replication, and histone chaperoning. These pleiotropic functions rely on NPM1’s ability to shuttle between nucleolar, nuclear, and cytoplasmic compartments. NPM1c mutations disrupt nucleolar localization signals through alterations of critical C-terminal tryptophan residues, resulting in mislocalization to the cytoplasm. This impairs NPM1’s interactions with nuclear protein partners and leads to dysregulation of processes such as apoptosis, DNA repair, and differentiation. In addition, NPM1c has been shown to acquire novel functions, including binding to chromatin and promoting oncogene expression. However, how these gain- and loss-of-function effects cooperate to drive leukemogenesis remains poorly understood. Importantly, NPM1 contains RNA-binding domains that remain intact in the mutant NPM1c protein. The contribution of NPM1c–RNA interactions to its leukemogenic function has not been investigated. To address this, we performed enhanced crosslinking and immunoprecipitation (eCLIP) experiments to define the RNA interactome of wild-type and mutant NPM1. Our preliminary data identified C/D box small nucleolar RNAs (snoRNAs) as prominent RNA species bound by NPM1c. Previous work from our group demonstrated that these snoRNAs are enriched in leukemia stem cells and are functionally essential. Functional studies revealed that deletion of the snoRNA-binding domain significantly impairs the oncogenic potential of NPM1c. Moreover, knockdown of a single NPM1c-associated snoRNA markedly reduced the self-renewal capacity of NPM1 mutant AML cells, while NPM1 wild-type AML cells remained unaffected. These findings suggest a previously unrecognized, functional relevance of NPM1c–snoRNA interactions in leukemogenesis. The proposed project aims to: 1. Define the functional consequences of the NPM1c–snoRNA interaction in AML development, 2. Elucidate the underlying regulatory mechanisms of NPM1c-snoRNA interactions, and 3. Evaluate the therapeutic potential of disrupting NPM1c–snoRNA interactions using snoRNA-specific antisense oligonucleotides modified with Locked Nucleic Acids (LNAs). In the long term, this project seeks to provide novel insights into RNA-driven oncogenic mechanisms and assess RNA-targeted therapeutic strategies for NPM1-mutant AML.

• DFG Programme: Research Grants