ORCID Profile
0000-0002-1678-5864
Current Organisations
Woods Hole Oceanographic Institution
,
St. Mary's University of Minnesota
,
Northwestern University
,
St. Jude Children's Research Hospital
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Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
Publisher: American Society of Hematology
Date: 04-06-2015
DOI: 10.1182/BLOOD-2015-02-626127
Abstract: Heterozygous alterations of Pax5, the most common target of genetic alteration in ALL, promote ALL in mouse mutagenesis models. Leukemia development is accompanied by the acquisition of genetic alterations commonly observed in human leukemia.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2022
DOI: 10.1038/S43018-022-00370-5
Abstract: DNA methylation is tightly regulated during development and is stably maintained in healthy cells. In contrast, cancer cells are commonly characterized by a global loss of DNA methylation co-occurring with CpG island hypermethylation. In acute lymphoblastic leukemia (ALL), the commonest childhood cancer, perturbations of CpG methylation have been reported to be associated with genetic disease subtype and outcome, but data from large cohorts at a genome-wide scale are lacking. Here, we performed whole-genome bisulfite sequencing across ALL subtypes, leukemia cell lines and healthy hematopoietic cells, and show that unlike most cancers, ALL s les exhibit CpG island hypermethylation but minimal global loss of methylation. This was most pronounced in T cell ALL and accompanied by an exceptionally broad range of hypermethylation of CpG islands between patients, which is influenced by TET2 and DNMT3B. These findings demonstrate that ALL is characterized by an unusually highly methylated genome and provide further insights into the non-canonical regulation of methylation in cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-02-2021
DOI: 10.1038/S41467-021-21255-8
Abstract: Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53 , and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2016
DOI: 10.1038/NG.3709
Publisher: Research Square Platform LLC
Date: 27-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 06-01-2021
DOI: 10.1158/2159-8290.CD-20-1230
Abstract: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing & .2 petabytes of raw genomic data from & ,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community. This article is highlighted in the In This Issue feature, p. 995
Publisher: American Association for Cancer Research (AACR)
Date: 10-01-2020
DOI: 10.1158/0008-5472.BCD-19-0041
Abstract: This study defines the landscape of mutations that preexist and arise after commencement of ALL therapy and shows that relapse may be propagated from ancestral, major, or minor clones at initial diagnosis. A subset of cases exhibits hypermutation that results in expression of neoepitopes that may be substrates for immunotherapeutic intervention. See related video: 42838617 See related commentary by Ogawa, p. 21. See related article by S. Dobson et al . This article is highlighted in the In This Issue feature, p. 5
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1038/NATURE10725
Publisher: American Society of Hematology
Date: 17-01-2013
DOI: 10.1182/BLOOD-2012-04-422691
Abstract: One recently identified subtype of pediatric B-precursor acute lymphoblastic leukemia (ALL) has been termed BCR-ABL1–like or Ph-like because of similarity of the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor outcome. Prior studies demonstrated that approximately half of these patients had genomic lesions leading to CRLF2 overexpression, with half of such cases harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine whether mutations in other tyrosine kinases might also occur in ALL, we sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with either a Ph-like gene expression profile or other alterations suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3 mutation, no somatic mutations were found in any other tyrosine kinases, suggesting that alternative mechanisms are responsible for activated kinase signaling in high-risk ALL.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Massachusetts Medical Society
Date: 11-09-2014
Publisher: American Society of Hematology
Date: 02-04-2019
DOI: 10.1182/BLOODADVANCES.2018030635
Abstract: Recent studies have identified germline mutations in TP53, PAX5, ETV6, and IKZF1 in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown despite mutational analysis of the exome. Here, we report a germline deletion of ETV6 identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the ETV6 exon 7 splice acceptor, resulting in exon skipping and protein truncation. The ETV6 deletion was also identified by optimal structural variant analysis of exome sequencing data. These findings identify a new mechanism of germline predisposition in ALL and implicate ETV6 germline variation in predisposition to lymphoma. Importantly, these data highlight the importance of germline structural variant analysis in the search for germline variants predisposing to familial leukemia.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2015
DOI: 10.1038/NG.3230
Publisher: Research Square Platform LLC
Date: 30-10-2023
Publisher: Springer Science and Business Media LLC
Date: 24-10-2016
DOI: 10.1038/NG.3691
Publisher: Springer Science and Business Media LLC
Date: 04-05-2015
DOI: 10.1038/NMETH.3394
Publisher: Elsevier BV
Date: 05-2018
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1038/NATURE10733
Publisher: Springer Science and Business Media LLC
Date: 19-03-2015
DOI: 10.1038/NCOMMS7604
Abstract: There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal ersity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2 , CREBBP , WHSC1 , TP53 , USH2A , NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
Publisher: Ubiquity Press, Ltd.
Date: 2023
DOI: 10.5334/AOGH.4331
Publisher: Ubiquity Press, Ltd.
Date: 2023
DOI: 10.5334/AOGH.4056
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 09-2022
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
DOI: 10.1038/S41467-017-01590-5
Abstract: Myelodysplastic syndromes (MDS) are uncommon in children and have a poor prognosis. In contrast to adult MDS, little is known about the genomic landscape of pediatric MDS. Here, we describe the somatic and germline changes of pediatric MDS using whole exome sequencing, targeted licon sequencing, and/or RNA-sequencing of 46 pediatric primary MDS patients. Our data show that, in contrast to adult MDS, Ras/MAPK pathway mutations are common in pediatric MDS (45% of primary cohort), while mutations in RNA splicing genes are rare (2% of primary cohort). Surprisingly, germline variants in SAMD9 or SAMD9L were present in 17% of primary MDS patients, and these variants were routinely lost in the tumor cells by chromosomal deletions (e.g., monosomy 7) or copy number neutral loss of heterozygosity (CN-LOH). Our data confirm that adult and pediatric MDS are separate diseases with disparate mechanisms, and that SAMD9/SAMD9L mutations represent a new class of MDS predisposition.
Publisher: American Society of Hematology
Date: 15-09-2011
DOI: 10.1182/BLOOD-2011-03-341412
Abstract: We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets.
Publisher: American Society of Hematology
Date: 21-01-2021
Abstract: There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2012
DOI: 10.1038/NG.1102
Publisher: American Society of Hematology
Date: 16-03-2023
Abstract: Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 in iduals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected in idual aged & years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for the identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk variants in 28 pedigrees, of which 33 are coding and 11 are noncoding. The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5′ untranslated region variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A& C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2611
Publisher: Springer Science and Business Media LLC
Date: 08-09-2013
DOI: 10.1038/NG.2754
Publisher: Public Library of Science (PLoS)
Date: 23-06-2015
Publisher: Ubiquity Press, Ltd.
Date: 2022
DOI: 10.5334/AOGH.3916
Publisher: Springer Science and Business Media LLC
Date: 2012
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Gang Wu.