Substantial heterogeneity within mutant TP53 AML and MDS-EB precludes the exact assessment of prognostic impact for individual patients. Here we performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing (NGS) on 2,200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics and mutant TP53 molecular minimal residual disease, and studied the associations of these characteristics with overall survival (OS). TP53 mutations were detected in 230 (10.5%) AML/MDS-EB patients with a median variant allele frequency (VAF) of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 were detected between AML and MDS-EB. Mutant TP53 patients have a very poor outcome (2-year OS, 12.8%), however no survival difference among AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival. In the majority of patients, TP53 mutations remained detectable in complete remission (CR) by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. In conclusion, mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.

The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in and in knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in , a key driver gene for both clonal hematopoiesis and AML. Our findings reveal genetic and epigenetic factors that shape the mutagenic influence of 5mC. Within blood cells, this links methylation damage to the driver landscape of clonal hematopoiesis and reveals a conserved path to leukemia. Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.