Publication Date
1-1-2022
Journal
Cancer Discovery
DOI
10.1158/2159-8290.CD-21-0560
PMID
34429321
PMCID
PMC8758508
PubMedCentral® Posted Date
8-24-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, DNA Methyltransferase 3A, HEK293 Cells, Humans, Leukemia, Myeloid, Acute, Leukocytes, Mononuclear, Mice, Mutation, Missense, Ubiquitin-Protein Ligases
Abstract
Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease.
Significance:
DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.