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The chromatin activation landscape of chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor immunoglobulin is currently unknown. Here, we report the results of a whole-genome chromatin profiling of histone 3 lysine 27 acetylation of 22 CLLs from major subsets which were compared against non-stereotyped CLLs and normal B cell subpopulations. Although subsets #1, #2, and #4 did not differ much from their non-stereotyped CLL counterparts, subset #8 displayed a remarkably distinct chromatin activation profile. In particular, we identified 209 de novo active regulatory elements in this subset, which showed similar patterns with U-CLLs undergoing Richter transformation. These regions were enriched for binding sites of 9 overexpressed transcription factors. In 78/209 regions, we identified 113 candidate overexpressed target genes, being 11 regions associated with more than two adjacent genes. These included blocks of up to 7 genes, suggesting a local co-upregulation within the same genome compartment. Our findings further underscore the uniqueness of subset #8 CLLs, notable for the highest risk of Richter's transformation amongst all CLL, and provide additional clues to decipher the molecular basis of its clinical behavior.

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype. This research was funded by the European Union's Seventh Framework Programme through the Blueprint Consortium (grant agreement 282510), Fundació La Marató de TV3, Instituto de Salud Carlos III (ISCIII) PI14/01867, PI16/02024, and PI17/00701, TRASCAN (EPICA), MINECO Explora (RTHALMY), Departamento de Salud del Gobierno de Navarra 40/2016, Gilead Fellowship Program (GLD16/00142), Multiple Myeloma Research Foundation Networks of excellence, the International Myeloma Foundation (Brian van Novis) and the Qatar National Research Fund award 7-916-3-237. Furthermore, the authors acknowledge the support of the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-736 and 2017-SGR-1142, TRASCAN-iMMunocelland European Research Council starting grant (MYELOMANEXT), CIBERONC (CB16/12/00489, CB16/12/00369 and CB16/12/00225), co-financed with FEDER funds, the Accelerator award CRUK/AIRC/AECC joint funder-partnership, as well as NCI R01 CA180475 and a MMRF collaborative grant. R.O. was supported by a FPU Fellowship of the Spanish Government, M.K. by an AOI grant of the Spanish Association Against Cancer and N.R. by the Acció instrumental d'incorporació de scientífics i tecnòlegs PERIS 2016 from the Generalitat de Catalunya. This work was partially developed at the Centro Esther Koplowitz (CEK, Barcelona, Spain). We particularly acknowledge the patients for their participation and the Biobank of the University of Navarra for its collaboration.