Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

Xu, Hong‐Xi; Zhang, Hui; Yang, Wenjian; Yadav, Rachita; Morrison, Alanna C.; Qian, Maoxiang; Devidas, Meenakshi; Liu, Yu; Pérez-Andreu, Virginia; Zhao, Xujie; Gastier‐Foster, Julie M.; Lupo, Philip J.; Neale, Geoffrey; Raetz, Elizabeth A.; Larsen, Eric; Bowman, W. Paul; Carroll, William L.; Winick, Naomi J.; Williams, Richard; Hansen, Torben; Holm, Jens Christian; Mardis, Elaine R.; Fulton, Robert S.; Pui, Ching Hon; Zhang, Jinghui; Mullighan, Charles G.; Evans, William E.; Hunger, Stephen P.; Gupta, Ramneek; Schmiegelow, Kjeld; Loh, Mignon L.; Relling, Mary V.; Yang, Jun J.

doi:10.1038/ncomms8553

Cited by 70 publications

(93 citation statements)

References 39 publications

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“…Viral particles were prepared using the calcium chloride method in HEK293T cells and stable knockdown was established in the human lymphoid cell line Nalm6 (German Collection of Microorganisms and Cell Cultures, DSMZ) by lentiviral transduction of shRNA and puromycin selection, following procedures described previously 61 . Cell lines were authenticated by karyotyping and cytogenetics and tested negative for mycoplasma contamination.…”

Section: Methodsmentioning

confidence: 99%

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

et al. 2016

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Widely used as anti-cancer and immunosuppressive agents, thiopurines have narrow therapeutic indices due to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and its clinical implications remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore, and Japan, we identified 4 NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, p.Val18_Val19insGlyVal) that resulted in 74.4%–100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across three cohorts (P=0.021, 2.1×10−5, and 0.0054, respectively; meta-analysis P=4.45×10−8, allelic effect size=−11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased its cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive thiopurine active metabolites and toxicity. Taken together, our results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.

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Section: Methodsmentioning

confidence: 99%

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

et al. 2016

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“…In vitro differentiation assay of mouse HSPCs EP300-, CREBBP-, TCF3-, and TAF15-ZNF384 transcripts were cloned into the pcL20c-IRES-GFP lentiviral vector, and lentiviral supernatants were produced by transient transfection of HEK293T cells using calcium phosphate (Xu et al 2015). Lin…”

Section: Znf384 Target Gene Promoter and Enhancer Activity By Lucifermentioning

confidence: 99%

“…The NRAS G12D and CRLF2 constructs were gifts from Dr. Charles Mullighan at St. Jude Children's Research Hospital. Retroviral particles were produced using ecotropic HEK293T cells (American Type Culture Collection) (Xu et al 2015). Each experiment was performed three times.…”

Section: Sca1mentioning

confidence: 99%

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

et al. 2016

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Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP. ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300-and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.

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“…Different underlying causes for the second, crucial step in the natural history of ALL (gene deletions or mutations that cause ALL) have been postulated, including aberrant reactions to infections in infancy and genetic variation in immune-response pathways (1). Germline variation can influence either step in this process, and case-control GWA studies have successfully identified ALL-associated SNPs in genes including ARID5B, IKZF1, CEBPE, PIP4K2A, CDKN2A/2B, and GATA3 (8–15). Supplementary Table S1 shows genes containing variants that have been associated with ALL in at least two GWA studies at a genome-wide significant level ( p < 5 x 10 −8 ).…”

Section: Introductionmentioning

confidence: 99%

“…To identify genes and gene subnetworks influencing genetic predisposition for ALL, we analyzed two datasets of p -values from previously published case-control ALL GWA studies (14,15) and p -values from an ALL case-parent trio study (25,26). We used the gene-level association method PEGASUS (20) to identify novel candidate genes associated with ALL.…”

Section: Introductionmentioning

confidence: 99%

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

Nakka

Archer

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, suggesting that germline variants influence ALL risk. Although multiple genome-wide association (GWA) studies have identified variants predisposing children to ALL, it remains unclear whether genetic heterogeneity affects ALL susceptibility and how interactions within and among genes containing ALL-associated variants influence ALL risk. Methods Here we jointly analyze two published datasets of case-control GWA summary statistics along with germline data from ALL case-parent trios. We use the gene-level association method PEGASUS to identify genes with multiple variants associated with ALL. We then use PEGASUS gene scores as input to the network analysis algorithm HotNet2 to characterize the genomic architecture of ALL. Results Using PEGASUS, we confirm associations previously observed at genes such as ARID5B, IKZF1, CDKN2A/2B, and PIP4K2A, and we identify novel candidate gene associations. Using HotNet2, we uncover significant gene subnetworks that may underlie inherited ALL risk: a subnetwork involved in B-cell differentiation containing the ALL-associated gene CEBPE; and a subnetwork of homeobox genes including MEIS1. Conclusions Gene and network analysis uncovers loci associated with ALL that are missed by GWA studies such as MEIS1. Further, ALL-associated loci do not appear to interact directly with each other to influence ALL risk, and instead appear to influence leukemogenesis through multiple, complex pathways. Impact We present a new pipeline for post-hoc analysis of association studies that yields new insight into the etiology of ALL, and can be applied in future studies to shed light on the genomic underpinnings of cancer.

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Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

Cited by 70 publications

References 39 publications

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

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