Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype

Großmann, Vera; Tiacci, Enrico; Holmes, Antony B.; Kohlmann, Alexander; Martelli, Maria Paola; Kern, Wolfgang; Spanhol-Rosseto, Ariele; Klein, Hans-Ulrich; Dugas, Martin; Schindela, Sonja; Трифонов, Владимир; Schnittger, Susanne; Haferlach, Claudia; Bassan, Renato; Wells, Victoria A.; Spinelli, Orietta; Chan, Joseph M.; Rossi, Roberta; Baldoni, Stefano; Carolis, Luca De; Goetze, Katharina; Serve, Hubert; Peceny, Rudolf; Kreuzer, Karl‐Anton; Oruzio, Daniel; Specchia, Giorgina; Raimondo, Francesco Di; Fanfani, Francesco; Sborgia, Marco; Liso, Arcangelo; Farinelli, Laurent; Rambaldi, Alessandro; Pasqualucci, Laura; Rabadán, Raúl; Haferlach, Torsten; Falini, Brunangelo

doi:10.1182/blood-2011-07-365320

Cited by 221 publications

(201 citation statements)

References 41 publications

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“…Furthermore, by using another tissue type, we tested whether this phenomenon is also seen in other tissue types. BCOR encodes the BLC6 co-repressor protein previously linked to certain cancers 24,25 and was selected as the gene overlapped 25 HM450 probes showing a distinct Xa-specific methylation pattern and had the most extensive probe coverage on the X chromosome after XIST. The placenta was chosen as it represents the extraembryonic lineage, whereas blood is mesodermal and buccal ectodermal in origin, enabling us to test whether this Xa-specific pattern in this region is limited to specific tissue types.…”

Section: Resultsmentioning

confidence: 99%

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Human active X-specific DNA methylation events showing stability across time and tissues

et al. 2014

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The phenomenon of X chromosome inactivation in female mammals is well characterised and remains the archetypal example of dosage compensation via monoallelic expression. The temporal series of events that culminates in inactive X-specific gene silencing by DNA methylation has revealed a 'patchwork' of gene inactivation along the chromosome, with approximately 15% of genes escaping. Such genes are therefore potentially subject to sex-specific imbalance between males and females. Aside from XIST, the non-coding RNA on the X chromosome destined to be inactivated, very little is known about the extent of loci that may be selectively silenced on the active X chromosome (Xa). Using longitudinal array-based DNA methylation profiling of two human tissues, we have identified specific and widespread active X-specific DNA methylation showing stability over time and across tissues of disparate origin. Our panel of X-chromosome loci subject to methylation on Xa reflects a potentially novel mechanism for controlling female-specific X inactivation and sex-specific dimorphisms in humans. Further work is needed to investigate these phenomena.

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Section: Resultsmentioning

confidence: 99%

“…However, we cannot rule out that BCOR Xa methylation has a role in sexual dimorphic gene expression in specific cell types or below the detection level of our sample size. We note that BCOR is subject to recurrent somatic point mutations 24,25 or translocations 28,29 in a range of cancer sub-types.…”

Section: Xa-specific Methylation Is Associated With Genesmentioning

confidence: 99%

Human active X-specific DNA methylation events showing stability across time and tissues

et al. 2014

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“…In over half the JAK2SB vav leukemias, transposon insertion into both Erg and Ets1 was evident, suggesting that co-occurrence of activation of these ETS family proteins may serve to reinforce the maturation block that contributes to erythroid transformation. In addition to Erg and Ets1, CIS in JAK2SB vav leukemias were identified at several additional loci with known links to hematological malignancies, including Zmiz1, a gene fusion partner of Abl oncogene 1 (ABL1) (27), Bcor, a transcriptional corepressor mutated in AML (28), and Vav1, commonly deregulated in lymphoid malignancy (29), suggesting that these genes might also contribute to erythroleukemia development.…”

Section: Discussionmentioning

confidence: 99%

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Tang

Carmichael

Shi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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To define genetic lesions driving leukemia, we targeted credependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of bipotential erythro-megakaryocytic cells. The genes encoding the E-twenty-six (ETS) transcription factors Ets related gene (Erg) and Ets1 were the most common sites for transposon insertion in SB-induced JAK2V617F-positive erythroleukemias, present in 87.5% and 65%, respectively, of independent leukemias examined. The role of activated Erg was validated by reproducing erythroleukemic pathology in mice transplanted with fetal liver cells expressing translocated in liposarcoma (TLS)-ERG, an activated form of ERG found in human leukemia. Via application of SB mutagenesis to TLS-ERG-induced erythroid transformation, we identified multiple loci as likely collaborators with activation of Erg. Jak2 was identified as a common transposon insertion site in TLS-ERG-induced disease, strongly validating the cooperation between JAK2V617F and transposon insertion at the Erg locus in the JAK2V617F-positive leukemias. Moreover, loci expressing other regulators of signal transduction pathways were conspicuous among the common transposon insertion sites in TLS-ERGdriven leukemia, suggesting that a key mechanism in erythroleukemia may be the collaboration of lesions disturbing erythroid maturation, most notably in genes of the ETS family, with mutations that reduce dependence on exogenous signals.T he study of cancer-causing genes using insertional mutagenesis in the mouse (1, 2) provides a powerful complement to human cancer genomics for functional identification and characterization of the genetic lesions driving tumor development. Transposons are DNA elements with the unique capacity to change their genomic position, usually via expression of a transposase, an enzyme that catalyzes excision of the transposon from the genome and facilitates its reintegration elsewhere. Although most mammals lack active endogenous transposons, the Sleeping Beauty (SB) system has been developed recently to adapt the well-studied fish Tc/mariner transposon to allow insertional mutagenesis in the mouse (2). Temporally controlled or tissue-specific SB-mediated genetic screens have been designed by imposing cre-recombinase control over the expression of the transposase (2). Moreover, by activating transposition in mice carrying a predisposing germ-line genetic lesion, insertional mutations that cooperate with that particular lesion in cancer pathogenesis can be isolated specifically.To define genetic lesions driving leukemia, we targeted SB transposon mutagenesis to the blood-forming system by intercrossing mice transgenic for both a transposon array and a cre-inducible ...

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“…Since 2011, somatic BCOR mutations have been detected using whole-exome sequencing in 3.8% unselected patients with AML with normal karyotypes (CN-AML), 4.2% patients with myelodysplastic syndrome (MDS), and 7.4% patients with chronic myelomonocytic leukemia (CMML; 3A (DNMT3A) and runt-related transcription factor 1 (RUNX1) mutations were detected in 43.5% and 44.4% patients with BCOR-mutated AML, respectively (20). Remarkably, BCOR mutations have been associated with poor prognosis in patients with CN-AML and MDS (20,21).…”

Section: Somatic Bcor Mutations In a Broad Range Of Human Cancersmentioning

confidence: 99%

“…Remarkably, BCOR mutations have been associated with poor prognosis in patients with CN-AML and MDS (20,21). In male patients with AML, BCOR mutations disrupted the single gene allele, whereas in female patients with AML, the mutations selectively targeted the functional allele because the exclusive expression of mutated BCOR was detected by cDNA-based amplicon deep sequencing (20).…”

Section: Somatic Bcor Mutations In a Broad Range Of Human Cancersmentioning

confidence: 99%

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Yamamoto

Abe

Emi

2014

Molecular Cancer Research

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The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCORlike 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479-84. Ó2014 AACR. IntroductionA major cause of developmental diseases and cancers is the dysregulation of proper transcriptional control, a process that is directly regulated by transcription factors, coactivators, and corepressors. Till date, several hundred transcriptional coregulators have been reported in the literature. Recently, the increased use of massively parallel sequencing techniques has expanded our knowledge on the induction of congenital diseases and cancers caused by specific gene mutations.

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Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype

Cited by 221 publications

References 41 publications

Human active X-specific DNA methylation events showing stability across time and tissues

Human active X-specific DNA methylation events showing stability across time and tissues

Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

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