Details

Autor(en) / Beteiligte

• Sanders, Mathijs A.
• Chew, Edward
• Flensburg, Christoffer
• Zeilemaker, Annelieke
• Miller, Sarah E.
• al Hinai, Adil S.
• Bajel, Ashish
• Luiken, Bram
• Rijken, Melissa
• Mclennan, Tamara
• Hoogenboezem, Remco M.
• Kavelaars, François G.
• Fröhling, Stefan
• Blewitt, Marnie E.
• Bindels, Eric M.
• Alexander, Warren S.
• Löwenberg, Bob
• Roberts, Andrew W.
• Valk, Peter J.M.
• Majewski, Ian J.

Titel

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

Ist Teil von

• Blood, 2018-10, Vol.132 (14), p.1526-1534

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •The DNA glycosylase MBD4 acts as a safeguard against damage from 5mC deamination.•Germ line MBD4 deficiency stimulates clonal hematopoiesis and guides the development of leukemia via recurrent mutations in DNMT3A. [Display omitted]