Missense Mutations in Myc Box I Influence Nucleocytoplasmic Transport to Promote Leukemogenesis

Area of Science:

• Hematology
• Molecular Biology
• Cancer Genetics

Background:

• Somatic missense mutations in the MYC gene's phosphodegron domain (MYC Box I or MBI) are found in acute myeloid leukemia (AML) clones.
• The precise mechanisms by which these MBI MYC mutations contribute to AML pathogenesis remain largely unknown.

Purpose of the Study:

• To investigate the functional and molecular effects of MBI MYC mutations in hematopoietic cells.
• To compare the consequences of expressing wild-type MYC versus oncogenic MBI mutant MYC proteins.
• To develop and utilize a mouse model for studying germline MBI MYC mutations in vivo.

Main Methods:

• Multi-omic analysis of hematopoietic cells expressing wild-type and mutant MYC.
• Development of a knockin mouse model harboring the Myc p.T58N germline mutation.
• Comparative analysis of cellular phenotypes, gene expression, and protein localization.

Main Results:

• Both wild-type and MBI mutant MYC proteins enhance hematopoietic progenitor cell self-renewal and expansion.
• MBI mutant MYC-expressing cells exhibit reduced apoptosis and accelerated leukemogenesis compared to wild-type.
• Mutant MYC alters mRNA translation, impacting proapoptotic and immune-regulatory genes, and increases RNA-binding proteins and nuclear export machinery.
• Mutant MYC proteins show increased aggregation in perinuclear and cytoplasmic regions.
• Knockin mice recapitulate key features, including altered MYC localization, progenitor expansion, and hematopoietic tumor development.

Conclusions:

• MBI MYC mutations contribute to hematopoietic malignancies by dysregulating RNA nucleocytoplasmic transport.
• These findings reveal a novel mechanism linking MYC mutations to altered RNA processing in AML.
• Targeting RNA transport pathways may offer new therapeutic strategies for AML with MBI MYC mutations.