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This work was partially developed at the Centro Esther Koplowitz (Barcelona, Spain). This research was funded by the Accelerator award Cancer Research UK/Italian Association for Cancer Research/Spanish Association Against Cancer joint funder partnership (J.I.M.-S.), Generalitat de Catalunya Suport Grups de Recerca AGAUR (2021-SGR-1343 [J.I.M.-S.], 2021-SGR-01172 [E.C.], and 2021-SGR-01293 [S.B.]), la Caixa Foundation (CLLEvolution, LCF/PR/HR17/52150017 [HR17-00221LCF] and CLLSYSTEMS- LCF/PR/HR22/52420015 [HR22-00172] Health Research 2017 and 2022 Programs, [E.C.]), Force Hemato (grant reference: 03-2022), French Innovative Leukemia Organization group, Association des Cytogeneticiens de Langue Francaise (grant 2022) and SIRIC-CURAMUS (Cancer United research Associating Medecine, University and Society; grant reference: INCa-DGOS-INSERM_12560, INCa-DGOS-INSERM-ITMO Cancer_18010, and INCa-DGOS-INSERM-ITMO Cancer_18002). M.D.-F. is supported by a postdoctoral grant from the Spanish Association Against Cancer. J.C.S. was supported by research grants from the Kay Kendall Leukemia Fund, and Cancer Research UK (Early Cancer Research Initiative Network on MBL-M3 Accelerator award C42023/A29370).

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Epigenetic features support the diagnosis of B-cell prolymphocytic leukemia and identify 2 clinicobiological subtypes

Publicated to:Blood Advances. 8 (24): 6297-6307 - 2024-12-24 8(24), DOI: 10.1182/bloodadvances.2024013327

Authors: Charalampopoulou, Stella; Chapiro, Elise; Nadeu, Ferran; Zenz, Thorsten; Bea, Silvia; Martinez-Farran, Ares; Aymerich, Marta; Rozman, Maria; Roos-Weil, Damien; Bernard, Olivier; Susin, Santos A; Parker, Helen; Walewska, Renata; Oakes, Christopher C; Strefford, Jonathan C; Campo, Elias; Matutes, Estela; Duran-Ferrer, Marti; Nguyen-Khac, Florence; Martin-Subero, Jose I

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Abstract

The recognition of B-cell prolymphocytic leukemia (B-PLL) as a separate entity is controversial based on the current classification systems. Here, we analyzed the DNA methylome of a cohort of 20 B-PLL cases diagnosed according to the guidelines of the International Consensus Classification/Fourth revised edition of the World Health Organization Classification, and compared them with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), splenic marginal zone lymphoma (SMZL), and normal B-cell subpopulations. Unsupervised principal component analyses suggest that B-PLL is epigenetically distinct from CLL, MCL, and SMZL, which is further supported by robust differential methylation signatures in B-PLL. We also observe that B-PLL can be segregated into 2 epitypes with differential clinicobiological characteristics. B-PLL epitype 1 carries lower immunoglobulin heavy variable somatic hypermutation and a less profound germinal center-related DNA methylation imprint than epitype 2. Furthermore, epitype 1 is significantly enriched in mutations affecting MYC and SF3B1, and displays DNA hypomethylation and gene upregulation signatures enriched in MYC targets. Despite the low sample size, patients from epitype 1 have an inferior overall survival than those of epitype 2. This study provides relevant insights into the biology and differential diagnosis of B-PLL, and potentially identifies 2 subgroups with distinct biological and clinical features.

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