biostudies-literatureFreie BNHLBI NIH HHSNational Cancer InstituteNHGRI NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSOffice of Research Infrastructure Programs253-272https://www.ebi.ac.uk/biostudies/studies/S-EPMC11065175biostudies-literatureUnknown38(5-6)Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous <i>c-Myc</i> locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cellsGenes & developmentA germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies.PMC11065175R35 CA231989S10OD028685DP2 HG012442P01 HL084205S10 OD028685P01HL084205DP2-HG012442Carroll PARamani VEisenman RNRamsey ELFreie BVarnum-Finney BJBernstein IfalseA germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies.Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous <i>c-Myc</i> locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells2024-01-01T00:00:00Z2024 Apr2026-06-05T22:37:19.775Z2026-05-23T03:10:37.311ZS-EPMC110651753856524910.1101/gad.351292.123