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A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies
Brian Freie1, Patrick A Carroll1, Barbara J Varnum-Finney2
1Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle WA, USA.
Biorxiv : the Preprint Server for Biology
|November 14, 2023
Summary
A single point mutation in the MYC gene (MYC-T58A) in mice leads to increased self-renewal in hematopoietic progenitors, causing lymphomas and leukemias. This highlights MYC
Area of Science:
- * Molecular Biology
- * Cancer Biology
- * Hematopoiesis
Background:
- * Oncogenic activation of MYC in cancers typically involves increased transcription, not coding mutations.
- * MYC-dependent lymphomas often have point mutations in the MYC phospho-degron, specifically at threonine-58 (T58).
- * T58 phosphorylation normally targets MYC for degradation by the FBW7 ubiquitin ligase.
Conclusions:
- * A single point mutation rendering MYC non-phosphorylatable at T58 is sufficient to induce a gain-of-function phenotype.
- * This gain-of-function in multipotential hematopoietic progenitors is linked to increased self-renewal and the initiation of lymphomas and leukemias.
- * The study elucidates the critical role of MYC phosphorylation at T58 in regulating normal hematopoietic progenitor function and preventing oncogenesis.
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