Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma

Jin, Yi; Chen, Kenian; Paepe, Annick De; Hellqvist, Eva; Krstić, Aleksandra; Metang, Lauren A.; Gustafsson, Charlotte; Davis, R. Eric; Levy, Yair; Surapaneni, Rakesh; Wallblom, Ann; Nahi, Hareth; Månsson, Robert; Lin, Yin

doi:10.1182/blood-2017-09-808063

Cited by 78 publications

(107 citation statements)

References 47 publications

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“…By contrast, chromothripsis, chromoplexy and unspecified complex events had a similar contribution to gain- and loss-of-function hotspots (Wilcoxon rank sum test, Bonferroni-Holm adjusted p-values > 0.05). Strikingly, gain-of-function hotspots showed 5.5-fold enrichment of super-enhancers as compared with the remaining mappable genome (1.6 vs 0.3 super-enhancers per Mb, Poisson test p < 0.001)( Methods ) 40 . Enhancer peaks (H3K27ac) clustered around the SV breakpoints were observed in 46 out of 62 gain-of-function hotspots (74 %) ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

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Revealing the impact of recurrent and rare structural variants in multiple myeloma

Rustad

Yellapantula

Glodzik

et al. 2019

Preprint

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53The landscape of structural variants (SVs) in multiple myeloma remains poorly 54 understood. Here, we performed comprehensive classification and analysis of SVs in 55 multiple myeloma, interrogating a large cohort of 762 patients with whole genome and 56 RNA sequencing. We identified 100 SV hotspots involving 31 new candidate driver 57 genes, including drug targets BCMA (TNFRSF17) and SLAMF7. Complex SVs, 58 including chromothripsis and templated insertions, were present in 61 % of patients and 59 frequently resulted in the simultaneous acquisition of multiple drivers. After accounting 60 for all recurrent events, 63 % of SVs remained unexplained. Intriguingly, these rare SVs 61were associated with up to 7-fold enrichment for outlier gene expression, indicating that 62 many rare driver SVs remain unrecognized and are likely important in the biology of 63 individual tumors. 64 65 whole chromosome gains later in tumor evolution 13,20 . The second category is made up of 89 all other recurrent copy number alterations (CNAs), one or more of which are present in 90 virtually all patients 19,20 . Among these, gain of chromosome 1q21 often occurs early in 91 tumor evolution, while loss of tumor suppressor genes tends occur later 20-23 . The 92 structural basis of these established drivers remains poorly understood, and there is a lack 93 of data about the role of SVs beyond the most recurrent aberrations. 94We recently reported the first comprehensive SV characterization using WGS of 95 sequential samples from 30 multiple myeloma patients 20 . Despite the small sample set, 96SVs emerged as key drivers during all evolutionary phases of disease, and we identified a 97 high prevalence of three main classes of complex SVs: chromothripsis, templated 98 insertions and chromoplexy 20 . In chromothripsis, chromosomal shattering and random 99 rejoining results in a pattern of tens to hundreds of breakpoints with oscillating copy 100 number across one or more chromosomes 24 . Templated insertions are characterized by 101 focal gains bounded by translocations, resulting in concatenation of amplified segments 102 from two or more chromosomes into a continuous stretch of DNA, which is inserted back 103 into any of the involved chromosomes 2,20 . Chromoplexy similarly connects segments 104 from multiple chromosomes, but the local footprint is characterized by copy number 105 loss 25 . Importantly, complex SVs represent large-scale genomic alterations acquired by 106 the cancer cell at a single point in time, potentially driving subsequent tumor evolution. 107Here, we present the first comprehensive study of SVs in a large series of 762 108 multiple myeloma patients. We show that recurrent and rare SVs are critical in shaping 109 the genomic landscape of multiple myeloma, including complex events simultaneously 110 causing multiple drivers. 111 6 112 Results 113 Genome-wide landscape of structural variation in multiple myeloma 114To define the landscape of simple and complex SVs in multiple myeloma, we 115 investigated 762 newly di...

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Section: Resultsmentioning

confidence: 99%

“…Active enhancer (H3K27ac) and super-enhancer data from primary multiple myeloma cells was obtained from 40 . Enrichment of super-enhancers in hotspots was assessed using a Poisson test, comparing the super-enhancer density within 100 kb of hotspots with the remaining mappable genome.…”

Section: Methodsmentioning

confidence: 99%

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Rustad

Yellapantula

Glodzik

et al. 2019

Preprint

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“…Normal plasma cells are enriched in 5hmC at BTNL8, C11orf80, ITM2C, PSG4 and TRIO genes ( Figure 2B, 2C). We found high 5hmC signal together with H3K27ac and ATAC signals 39 at several important genes implicated in MM including CCND1, FGFR3 -MMSET, IRF4, PRDM1 and XBP1 ( Supplementary Figures 6A-F). Specifically, H3K27ac super-enhancers from a patient with t(4;14), del13 and amp1q from Jin and colleagues 39 and the 5hmC peak clusters found in one of our patients with the same genomic alterations are located at similar genomic loci CREB3L2, FNDC3B, MMSET, ST6GAL1 and ZBTB38 ( Supplementary Figures 5E,F).…”

Section: The 5hmc Regions Landscape In MMmentioning

confidence: 89%

“…Both 5hmC signals correlate well with CCND2 RNA expression and both regions are located in the same topogical domain according to HiC data 47,48 (chr12:3,850,000-4,800,000; Supplementary Figure 4B). The upstream region is also marked by ATAC and H3K27ac signals in MM patients 39 suggesting that this genomic region is functionally active. This strongly suggests that this upstream region is an enhancer of CCND2 gene.…”

Section: The 5hmc Regions Landscape In MMmentioning

confidence: 99%

“…ChIP-seq and ATAC-seq libraries were downloaded from the European Nucleotide Archive (project number PR-JEB25605 39 ) and treated with the pyflow-ChIPseq 40 and pyflow-ATACseq pipelines respectively with default parameters. Chromatine-states genome annotation was realized using ChromHMM 41 on ChIP-seq data from MM.1S cell line.…”

Section: Chip-seq and Atac-seq Analysismentioning

confidence: 99%

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DNA hydroxymethylation reveals transcription regulation networks and prognostic signatures in multiple myeloma

Alberge

Magrangeas

Wagner

et al. 2019

Preprint

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Key Points :• 5hmC is globally depleted in MM and even more in advanced stages of the disease.• 5hmC is locally detected at transcriptionally active regions of MM where its presence can be associated with survival. AbstractMultiple myeloma (MM) is a plasma cell malignancy that remains challenging to cure despite a substantially improving median survival. During the last decade, DNA copy number variation and gene expression studies have described the pathology and its heterogeneity among patients. Epigenetic modifications play important roles in MM, but they are rarely associated with clinical aspects of the disease. In this epigenomics study, we produced quantifications of genomic 5-methylcytosine (5mC) and of 5-hydroxymethylcytosine (5hmC) as well as genome-wide maps of hydroxymethylation to analyse myeloma cells taken from a cohort of 40 newly diagnosed and homogeneously treated patients. We found 5hmC to be globally depleted in MM compared to normal plasma cells, as well as being reduced in advanced clinical stages of the disease. From the hydroxymethylome data, we observed that remaining 5hmC is organised in large peak clusters and is associated with well-known disease-related genes. Based on their signal correlation, these 5hmC peak clusters can be gathered in 2 regulation networks involving core transcription factors such as IRF4, MYC, PRDM1 and TCF3. By performing paired hydroxymethylomes at diagnosis and at relapse, we found the disease progression to be heterogeneous and patient-specific. We found that the location of 5hmC at tumor suppressor TP53INP1 is associated with better outcome while global high level of 5hmC tends to be associated with better overall survival. Together, our study suggests that 5hmC provides new biological insights of the disease severity and progression, and can be used for retrospective studies. Correspondence:Aurélien Sérandour, ICO LABcT, Boulevard Jacques Monod, 44805 Saint Herblain, +33 (0)2 28 08 03 71 Stéphane Minvielle, IRS-UN, 8 quai Moncousu, 44000 Nantes, +33 (0)2 28 08 03 70 Methods Normal plasma cells purificationAfter informed consent, the femoral canal of individuals with isolated hip osteoarthritis who were otherwise healthy was probed with a metal suction device following femoral neck removal. Bone marrow cells were suctioned into a tube that contained EDTA, placed on ice and immediately transported to our laboratory. BMMCs were purified by Ficoll. Normal plasma cells were FACS-sorted using a BD FACSAria III as CD38/CD138 positive and CD3/CD13/CD33 negative (antibodies from Becton Dickinson, ref. 345807, 555332, 555394, 555450 and 562935). Myeloma cells purificationBone marrow biopsies were realized on MM newly diagnosed patients from cohort IFM-DFCI 2009 (Intergroupe Francophone du Myelome -Dana Farber Cancer Institute). 24, 25 All patients signed an informed consent form approved by the Toulouse Ethics Committee. All included patients were newly diagnosed with symptomatic MM based on International Myeloma Working Group 2003 Diagnostic Criteria. 24 All the samp...

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Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)

et al. 2021

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Approximately 20% of newly diagnosed multiple myeloma (NDMM) patients harbor t (11;14), a marker of inferior prognosis, resulting in up-regulation of CCND1. These patients respond to BCL2 inhibitor experimental drug venetoclax. Furthermore, t(11;14) is reported to be associated with increased BCL2/MCL1 ratio. We investigated the use of venetoclax (400 mg daily) in a cohort of 25 multiple myeloma (MM) and ALamyloidosis patients harboring t(11;14) and assessed safety and efficacy. Efficacy was assessed by response rate (RR) and time on treatment. Furthermore, immunohistochemistry (IHC), for BCL2 family member expression was assessed at diagnosis and relapse in the venetoclax-treated group and analyzed for correlation with clinical RR. Additionally, patient material from venetoclax non-treated group including non-t(11;14) diagnosis (n = 27), t(11;14) diagnosis (n = 17), t(11;14) relapse (n = 7), hyperdiploidy (n = 6) and hyperdiploidy + t(11;14) (n = 6) was used for RNA sequencing (RNASeq) and validation by qPCR. Venetoclax treatment in t(11;14) patients demonstrated manageable safety and promising efficacy. Partial responses or better were observed in eleven patients (44%). Responding patients had significantly higher BCL2/MCL1 (p = 0.031) as well as BCL2/BCL-XL (p = 0.021) ratio, regardless of time of measurement before venetoclax treatment. Furthermore, an IRF5 motif was enriched (p < .001) in the downregulated genes in t(11;14) relapses vs diagnoses. The RR with single agent venetoclax was 71% in AL-amyloidosis and 33% in MM, and IHC proved useful in prediction of treatment outcome. We could also demonstrate possible resistance mechanisms of t(11;14), downregulation of IRF5 targeted genes, which can be exploited for therapeutic advantages.

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Active enhancer and chromatin accessibility landscapes chart the regulatory network of primary multiple myeloma

Cited by 78 publications

References 47 publications

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Revealing the impact of recurrent and rare structural variants in multiple myeloma

DNA hydroxymethylation reveals transcription regulation networks and prognostic signatures in multiple myeloma

Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14)

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