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

被引：84

作者：

Sanders, Mathijs A. ^{[1
]}

Chew, Edward ^{[2
,3
,4
,5
]}

Flensburg, Christoffer ^{[2
,4
]}

Zeilemaker, Annelieke ^{[1
]}

Miller, Sarah E. ^{[2
]}

al Hinai, Adil S. ^{[1
,6
]}

Bajel, Ashish ^{[3
,5
]}

Luiken, Bram ^{[1
]}

Rijken, Melissa ^{[1
]}

McIennan, Tamara ^{[7
]}

Hoogenboezem, Remco M. ^{[1
]}

Kavelaars, Francois G. ^{[1
]}

Froehling, Stefan ^{[8
,9
,10
,11
]}

Blewitt, Marnie E. ^{[4
,7
]}

Bindels, Eric M. ^{[1
]}

Alexander, Warren S. ^{[2
,4
]}

Lowenberg, Bob ^{[1
]}

Roberts, Andrew W. ^{[2
,3
,4
,5
]}

Valk, Peter J. M. ^{[1
]}

Majewski, Ian J. ^{[2
,4
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[2] Walter & Eliza Hall Inst Med Res, Div Canc & Haematol, Parkville, Vic, Australia

[3] Royal Melbourne Hosp, Peter MacCallum Canc Ctr, Clin Hematol, Parkville, Vic, Australia

[4] Univ Melbourne, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia

[5] Victorian Comprehens Canc Ctr, Parkville, Vic, Australia

[6] Royal Hosp, Minist Hlth, Natl Genet Ctr, Muscat, Oman

[7] Walter & Eliza Hall Inst Med Res, Div Mol Med, Parkville, Vic, Australia

[8] Natl Ctr Tumor Dis Heidelberg, Div Translat Oncol, Heidelberg, Germany

[9] German Canc Res Ctr, Heidelberg, Germany

[10] German Canc Consortium, Heidelberg, Germany

[11] Heidelberg Univ Hosp, Sect Personalized Oncol, Heidelberg, Germany

来源：

BLOOD | 2018年 / 132卷 / 14期

基金：

美国国家卫生研究院; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

SOMATIC MUTATIONS; STEM-CELLS; CANCER; DNMT3A; GENE; DEAMINATION; MECHANISMS; SIGNATURES; PATTERNS; RISK;

D O I：

10.1182/blood-2018-05-852566

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 con- Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.

引用

页码：1526 / 1534

页数：9

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