Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Queirós, Ana C.; Beekman, Renée; Vilarrasa‐Blasi, Roser; Duran-Ferrer, Martí; Clot, Guillem; Merkel, Angelika; Raineri, Emanuele; Russiñol, Núria; Castellano, Giancarlo; Beà, Sı́lvia; Navarro, Alba; Kulis, Marta; Verdaguer-Dot, Núria; Jares, Pedro; Enjuanes, Anna; Calasanz, Marı́a José; Bergmann, Anke; Vater, Inga; Salaverría, Itziar; Werken, Harmen J.G. van de; Wilson, Wyndham H.; Datta, Avik; Flicek, Paul; Royo, Romina; Martens, Joost H.A.; Giné, Eva; López‐Guillermo, Armando; Stunnenberg, Hendrik G.; Klapper, Wolfram; Pott, Christiane; Heath, Simon; Gut, Marta; Siebert, Reiner; Campo, Elı́as; Martín‐Subero, José I.

doi:10.1016/j.ccell.2016.09.014

Cited by 110 publications

(124 citation statements)

References 53 publications

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“…Of particular interest was the observation of the structural activation of 6.1Mb affecting the entire chromosome band 2p25.2 in aggressive cMCL, which contains the SOX11 oncogene, a biomarker whose expression defines this MCL subtype 58 and plays key functional roles in its pathogenesis 80 . Although the SOX11 oncogene expression is related to the presence of active histone modifications in the promoter region 81 and the establishment of novel 3D loops with a distant enhancer element 32 , our finding indicates that such looping is embedded into long-range alterations in the 3D genome structure. This change is not only linked to SOX11 overexpression, but seems to be related to the simultaneous overexpression of multiple genes within the target region.…”

Section: Discussionmentioning

confidence: 67%

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Vilarrasa‐Blasi

Soler-Vila

Verdaguer-Dot

et al. 2019

Preprint

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Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

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Section: Discussionmentioning

confidence: 67%

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Vilarrasa‐Blasi

Soler-Vila

Verdaguer-Dot

et al. 2019

Preprint

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“…These patients exhibit unmutated IGHV gene rearrangement, SOX‐11 overexpression, a higher degree of genomic instability ( ATM , CDKN2A , chromatin modifier mutations are common), and other oncogenic mutations and epigenetic modifications. Additionally, naïve B cells here do not undergo germinal center reactions Leukemic non‐nodal MCL —This is seen in 10% to 20% MCL patients and commonly presents with lymphocytosis and splenomegaly.…”

Section: Advances In the Pathogenesis Of MCLmentioning

confidence: 99%

“…They have a clinical picture similar to CLL, may exhibit aberrant immunophenotype (CD200 expression, loss of CD5), and TLR2 and CCND1 mutations are overrepresented. A high number of DNA methylation changes or presence of oncogenic mutations in a subset can negatively impact the prognosis.…”

Section: Advances In the Pathogenesis Of MCLmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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“…21 With this in mind, and also considering that the tumor load of the analyzed samples could be as low as 70%, we performed in silico purification of the DNA methylation data after the pipeline previously described. 21,22 Data were analyzed with R using the "minfi" package 23 , available through the Bioconductor open source software. To exclude technical and biological biases that might produce false results in further analyses, we developed and optimized an analysis pipeline with several filters (i.e.…”

Section: Illumina 450k Dna Methylation Arrays and Data Analysismentioning

confidence: 99%

Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

Papakonstantinou

Ntoufa

Tsagiopoulou

et al. 2019

Intl Journal of Cancer

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Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U‐CLL). Subset #6 (IGHV1‐69/IGKV3‐20) is less aggressive compared to subset #8 (IGHV4‐39/IGKV1(D)‐39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome‐wide DNA methylation profiles in subsets #6 and #8 as well as other U‐CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U‐CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U‐CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro‐survival effect was also supported by siRNA‐mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.

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Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Cited by 110 publications

References 53 publications

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

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