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This study was supported by the la Caixa Foundation (CLLEvolution LCF/PR/HR17/52150017; Health Research 2017 Program HR17-00221) (E.C.), the European Research Council under the EU Horizon 2020 research and innovation program BCLLatlas 810287 (E.C.), the Instituto de Salud Carlos III and the European Regional Development Fund Una manera de hacer Europa (project PMP15/00007) (E.C.), the Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (E.C.), and CERCA Programme/Generalitat de Catalunya. F.N. is supported by a predoctoral fellowship of the Ministerio de Ciencia e Innovacio ' n (BES2016-076372). E.C. is an academia researcher of the Institucio ' Catalana de Recerca i Estudis Avancats of the Generalitat de Catalunya.

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IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics

Publicat a:Blood. 137 (21): 2935-2946 - 2021-05-27 137(21), DOI: 10.1182/blood.2020008311

Autors: Nadeu, Ferran; Royo, Romina; Clot, Guillem; Duran-Ferrer, Marti; Navarro, Alba; Martin, Silvia; Lu, Junyan; Zenz, Thorsten; Baumann, Tycho; Jares, Pedro; Puente, Xose S; Martin-Subero, Jose I; Delgado, Julio; Campo, Elias

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B-cell receptor (BCR) signaling is crucial for chronic lymphocytic leukemia (CLL) biology. IGLV3-21-expressing B-cells may acquire a single point mutation (R110) that triggers autonomous BCR signaling conferring aggressive behavior. Epigenetic studies have defined three CLL subtypes based on methylation signatures reminiscent of naïve-like (n-CLL), intermediate (i-CLL) and memory-like B-cells (m-CLL) with different biological features. i-CLL carry a borderline IGHV mutational load and a significant higher usage of IGHV3-21/IGLV3-21. To determine the clinical and biological features of IGLV3-21R110 CLL and its relationship to these epigenetic subtypes we have characterized the immunoglobulin gene of 584 CLL cases using whole-genome/exome and RNA sequencing. IGLV3-21R110 was detected in 6.5% of cases, being 30/79 (38%) i-CLL, 5/291 (1.7%) m-CLL and 1/189 (0.5%) n-CLL. All stereotype subset #2 cases carried IGLV3-21R110 while 62% of IGLV3-21R110 i-CLL had non-stereotyped B-cell receptor immunoglobulins. IGLV3-21R110 i-CLL had significantly higher number of SF3B1 and ATM mutations, and total number of driver alterations. Nonetheless, the R110 mutation was the sole alteration in one i-CLL and accompanied only by del(13q) in three. Although composite regarding IGHV mutational status, IGLV3-21R110 i-CLL transcriptomically resembled naïve-like/unmutated IGHV CLL with a specific signature including WNT5A/B overexpression. Contrarily, i-CLL lacking the IGLV3-21R110 mirrored memory-like/mutated IGHV cases. IGLV3-21R110 i-CLL had a short time to first treatment and overall survival similar to n-CLL/unmutated IGHV cases whereas non-IGLV3-21R110 i-CLL had a good prognosis similar to memory-like/mutated IGHV. Altogether, IGLV3-21R110 defines a CLL subgroup with specific biological features and an unfavorable prognosis independent of the IGHV mutational status and epigenetic subtypes.Copyright © 2020 American Society of Hematology.

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