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

Publication Date:
2018-10-05
Publisher:
American Society of Hematology (ASH)
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
Medicine
Keywords:
Hematopoiesis and Stem Cells, Myeloid Neoplasia
Published by:
http://www.hematology.org/
_version_ 1836399063124148225
autor Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
beschreibung 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.
citation_standardnr 6341097
datenlieferant ipn_articles
feed_id 310
feed_publisher American Society of Hematology (ASH)
feed_publisher_url http://www.hematology.org/
insertion_date 2018-10-05
journaleissn 1528-0020
journalissn 0006-4971
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Society of Hematology (ASH)
quelle Blood
relation http://www.bloodjournal.org/cgi/content/short/132/14/1526?rss=1
schlagwort Hematopoiesis and Stem Cells, Myeloid Neoplasia
search_space articles
shingle_author_1 Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
shingle_author_2 Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
shingle_author_3 Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
shingle_author_4 Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
shingle_catch_all_1 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
Hematopoiesis and Stem Cells, Myeloid Neoplasia
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.
Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_2 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
Hematopoiesis and Stem Cells, Myeloid Neoplasia
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.
Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_3 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
Hematopoiesis and Stem Cells, Myeloid Neoplasia
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.
Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_4 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
Hematopoiesis and Stem Cells, Myeloid Neoplasia
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.
Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., al Hinai, A. S., Bajel, A., Luiken, B., Rijken, M., Mclennan, T., Hoogenboezem, R. M., Kavelaars, F. G., Fröhling, S., Blewitt, M. E., Bindels, E. M., Alexander, W. S., Löwenberg, B., Roberts, A. W., Valk, P. J. M., Majewski, I. J.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_title_1 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
shingle_title_2 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
shingle_title_3 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
shingle_title_4 MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
timestamp 2025-06-30T23:37:00.339Z
titel MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
titel_suche MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
topic W
WW-YZ
uid ipn_articles_6341097