The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Andersson, AK; Ma, J; Wang, J; Chen, X; Gedman, AL; Dang, J; Nakitandwe, J; Holmfeldt, L; Parker, M; Easton, J; Huether, R; Kriwacki, R; Rusch, M; Wu, G; Li, Y; Mulder, H; Raimondi, S; Pounds, S; Kang, G; Shi, L; Becksfort, J; Gupta, P; Payne-Turner, D; Vadodaria, B; Boggs, K; Yergeau, D; Manne, J; Song, G; Edmonson, M; Nagahawatte, P; Wei, L; Cheng, C; Pei, D; Sutton, R; Venn, NC; Chetcuti, A; Rush, A; Catchpoole, D; Heldrup, J; Fioretos, T; Lu, C; Ding, L; Pui, C-H; Shurtleff, S; Mullighan, CG; Mardis, ER; Wilson, RK; Gruber, TA; Zhang, J; Downing, JR; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project,

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Andersson, AK Ma, J Wang, J Chen, X Gedman, AL Dang, J Nakitandwe, J Holmfeldt, L Parker, M Easton, J Huether, R Kriwacki, R Rusch, M Wu, G Li, Y Mulder, H Raimondi, S Pounds, S Kang, G Shi, L Becksfort, J Gupta, P Payne-Turner, D Vadodaria, B Boggs, K Yergeau, D Manne, J Song, G Edmonson, M Nagahawatte, P Wei, L Cheng, C Pei, D Sutton, R Venn, NC Chetcuti, A Rush, A Catchpoole, D Heldrup, J Fioretos, T Lu, C Ding, L Pui, C-H Shurtleff, S Mullighan, CG Mardis, ER Wilson, RK Gruber, TA Zhang, J Downing, JR St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project,

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Nat Genet, 2015, 47, (4), pp. 330-337
Issue Date:: 2015-04

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Field	Value	Language
dc.contributor.author	Andersson, AK
dc.contributor.author	Ma, J
dc.contributor.author	Wang, J
dc.contributor.author	Chen, X
dc.contributor.author	Gedman, AL
dc.contributor.author	Dang, J
dc.contributor.author	Nakitandwe, J
dc.contributor.author	Holmfeldt, L
dc.contributor.author	Parker, M
dc.contributor.author	Easton, J
dc.contributor.author	Huether, R
dc.contributor.author	Kriwacki, R
dc.contributor.author	Rusch, M
dc.contributor.author	Wu, G
dc.contributor.author	Li, Y
dc.contributor.author	Mulder, H
dc.contributor.author	Raimondi, S
dc.contributor.author	Pounds, S
dc.contributor.author	Kang, G
dc.contributor.author	Shi, L
dc.contributor.author	Becksfort, J
dc.contributor.author	Gupta, P
dc.contributor.author	Payne-Turner, D
dc.contributor.author	Vadodaria, B
dc.contributor.author	Boggs, K
dc.contributor.author	Yergeau, D
dc.contributor.author	Manne, J
dc.contributor.author	Song, G
dc.contributor.author	Edmonson, M
dc.contributor.author	Nagahawatte, P
dc.contributor.author	Wei, L
dc.contributor.author	Cheng, C
dc.contributor.author	Pei, D
dc.contributor.author	Sutton, R
dc.contributor.author	Venn, NC
dc.contributor.author	Chetcuti, A
dc.contributor.author	Rush, A
dc.contributor.author	Catchpoole, D
dc.contributor.author	Heldrup, J
dc.contributor.author	Fioretos, T
dc.contributor.author	Lu, C
dc.contributor.author	Ding, L
dc.contributor.author	Pui, C-H
dc.contributor.author	Shurtleff, S
dc.contributor.author	Mullighan, CG
dc.contributor.author	Mardis, ER
dc.contributor.author	Wilson, RK
dc.contributor.author	Gruber, TA
dc.contributor.author	Zhang, J
dc.contributor.author	Downing, JR
dc.contributor.author	St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project,
dc.date.accessioned	2022-04-11T04:36:29Z
dc.date.available	2015-02-02
dc.date.available	2022-04-11T04:36:29Z
dc.date.issued	2015-04
dc.identifier.citation	Nat Genet, 2015, 47, (4), pp. 330-337
dc.identifier.issn	1061-4036
dc.identifier.issn	1546-1718
dc.identifier.uri	http://hdl.handle.net/10453/156057
dc.description.abstract	Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation.ispartof	Nat Genet
dc.relation.isbasedon	10.1038/ng.3230
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Developmental Biology
dc.subject.mesh	Allelic Imbalance
dc.subject.mesh	Cohort Studies
dc.subject.mesh	DNA Mutational Analysis
dc.subject.mesh	Gene Frequency
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Mutation
dc.subject.mesh	Myeloid-Lymphoid Leukemia Protein
dc.subject.mesh	Oncogene Proteins, Fusion
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Protein-Tyrosine Kinases
dc.subject.mesh	Signal Transduction
dc.subject.mesh	ras Proteins
dc.subject.mesh	Humans
dc.subject.mesh	ras Proteins
dc.subject.mesh	Histone-Lysine N-Methyltransferase
dc.subject.mesh	Oncogene Proteins, Fusion
dc.subject.mesh	Cohort Studies
dc.subject.mesh	DNA Mutational Analysis
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Gene Frequency
dc.subject.mesh	Mutation
dc.subject.mesh	Allelic Imbalance
dc.subject.mesh	Infant
dc.subject.mesh	Myeloid-Lymphoid Leukemia Protein
dc.subject.mesh	Protein-Tyrosine Kinases
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.title	The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
dc.type	Journal Article
utslib.citation.volume	47
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	open_access	*
dc.date.updated	2022-04-11T04:36:26Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	47
utslib.citation.issue	4

Abstract:

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

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http://hdl.handle.net/10453/156057