Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies

Oyer, Jon A.; Huang, Xiaoxiao; Zheng, Yupeng; Shim, Joo-Cheol; Ezponda, Teresa; Carpenter, Zachary; Allegretta, Maddalena; Okot-Kotber, C. I.; Patel, Jay P.; Melnick, Ashley; Levine, Ross L.; Ferrando, Adolfo A.; MacKerell, Alexander D.; Kelleher, Neil L.; Licht, Jonathan D.

doi:10.1038/leu.2013.204

Cited by 125 publications

(125 citation statements)

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“…The analysis of WHSC1 and MEF2B in an expanded series confirmed the relative high frequency of these mutations in MCL (10% and 3.2%, respectively). WHSC1 mutations have not been described previously in lymphomas, but this gene is the target of the t(4;14) translocation in PCM, and the same mutation observed in exon 18 has been recently detected in an acute lymphoblastic leukemia (ALL) patient (30). The WHSC1 overexpression in PCM and the mutation in ALL seem to have an activating function because they increase the H3K36 methylation associated with a methylation decrease in H3K27 across the genome (15).…”

Section: Discussionmentioning

confidence: 99%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

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

463

361

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Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

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Section: Discussionmentioning

confidence: 99%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

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

463

361

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“…This hotspot mutation has been recurrently reported in mantle cell lymphoma 35 and in pediatric BCP-ALL 36,37 and results in cellular transformation. 36 The emergence of a clone carrying the WHSC1 E1099K mutation may have been sufficient to induce early relapse in this patient.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

et al. 2015

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Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition. ALL-BFM 86/90, 1989-1998 INS 98 protocol based on ALL-BFM 95 40 , 1998-2003 and ALL Intercontinental (IC) -BFM 200315, 2003-2005 analyzed at the time of primary diagnosis, during remission and at relapse. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n Methods Patients' clinical characteristicsPatients were treated according to ALL-BFM 2000 or related frontline protocols 14 IC 15 ). One patient was aged 18 at diagnosis, all others were children or adolescents. The 13 patients (Table 1) were recruited between 1993 and 2007 from the ALL-REZ BFM 2002 trials (patients T-ALL-H-A61, -E114, -F110, -KI17, -MD40, -T92, -T128) or from Schneider Children's Medical Center of Israel, Petah Tikva, Israel (patients T-ALL-H-S00169, -S00207, -S00285, -S00438, -S00456, -S00472) and selected on the basis of sufficient material being available from the time points of first diagnosis, remission and relapse. Minimal residual disease (MRD) response was assessed as described previously 2,16 (Online Supplementary Table S3).This study was approved by the institutional review boards of the Charité Universitätsmedizin Berlin and the Medical Faculty Heidelberg. Informed consent was obtained in accordance with the Declaration of Helsinki. Exome capture, target capture and Illumina sequencingThe Agilent SureSelect Target Enrichment Kit (Agilent...

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“…These and additional observations support a role for the NSD2 E1099K mutation as an epigenetic-mediated driver in the development of pediatric ALL. This mutation is also found in other cancers (20). Thus, NSD2 plays an important role during mammalian development and its overexpression or hyperactivity may cause cancer.…”

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confidence: 99%

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

Sankaran¹,

Wilkinson²,

Elias

et al. 2016

Journal of Biological Chemistry

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The readout of histone modifications plays a critical role in chromatin-regulated processes. Dimethylation at Lys-36 on histone H3 (H3K36me2) is associated with actively transcribed genes, and global up-regulation of this modification is associated with several cancers. However, the molecular mechanism by which H3K36me2 is sensed and transduced to downstream biological outcomes remains unclear. Here we identify a PWWP domain within the histone lysine methyltransferase and oncoprotein NSD2 that preferentially binds to nucleosomes containing H3K36me2. In cells, the NSD2 PWWP domain interaction with H3K36me2 plays a role in stabilizing NSD2 at chromatin. Furthermore, NSD2's ability to induce global increases in H3K36me2 via its enzymatic activity, and consequently promote cellular proliferation, is compromised by mutations within the PWWP domain that specifically abrogate H3K36me2-recognition. Together, our results identify a pivotal role for NSD2 binding to its catalytic product in regulating its cellular functions, and suggest a model for how this interaction may facilitate epigenetic spreading and propagation of H3K36me2.Chromatin dynamics play a critical role in the regulation of diverse cellular functions, the dysregulation of which is linked to the development and progression of human diseases. A major mechanism for regulating chromatin functional states involves the reversible covalent post-translational modification of histone proteins by chemical moieties such as methyl-, acetyl-, and phospho-groups. Histones provide a highly modifiable signaling surface on which these chemical marks combine to define particular chromatin states and regulate the extent of accessibility of DNA to trans-acting factors. In this context, the proteins and domains that recognize histone modification fundamentally influence DNA-templated processes, transducing molecular events at chromatin to biological outcomes. Protein lysine methylation is a principal chromatin-regulatory mechanism. The chemical addition of methyl moieties to lysine residues is catalyzed by lysine methyltransferases (KMTs).3 Lysine residues can accept up to three methyl groups forming mono-, di-, and tri-methylated derivatives (referred to as me1, me2, and me3, respectively). Histone methylation has been linked via methyllysine-binding proteins to diverse processes, including transcription, DNA recombination, DNA repair, and DNA replication.Methylation of histone H3 at lysine 36 (H3K36) is found at gene bodies of actively transcribed genes, but the state of methylation at this residue defines distinct biological outcomes. Trimethylation of this site (H3K36me3), which is mediated by the KMT SETD2 in humans, is involved in splicing regulation, RNA processing, and DNA damage signaling (1-7). Loss of SETD2 and H3K36me3 is a recurring phenomenon in clear cell renal cell carcinoma (ccRCC) and other cancers, suggesting a tumor suppressor role for SETD2 (8 -10). In contrast, the specific molecular functions associated with H3K36me2 are unclear. However, elevated level...

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Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies

Cited by 125 publications

References 15 publications

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin

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