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MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.

Abstract：

: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 MBD4 and in Mbd4 knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in DNMT3A, 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.

journal_name

Blood

journal_title

Blood

authors

Sanders MA,Chew E,Flensburg C,Zeilemaker A,Miller SE,Al Hinai AS,Bajel A,Luiken B,Rijken M,Mclennan T,Hoogenboezem RM,Kavelaars FG,Fröhling S,Blewitt ME,Bindels EM,Alexander WS,Löwenberg B,Roberts AW,Valk PJM,Majews

doi

10.1182/blood-2018-05-852566

subject

Has Abstract

pub_date

2018-10-04 00:00:00

pages

1526-1534

issue

14

eissn

0006-4971

issn

1528-0020

pii

blood-2018-05-852566

journal_volume

132

pub_type

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