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Chapiro, E.1, 2; Diop, K.3; Dessen, P.3; Roos-Weil, D.4, 5; Gabillaud, C.2; Pramil, E.1; Maloum, K.2; Settegrana, C.2; Baseggio, L.6; Davi, F.1, 2; Le Garff-Tavernier, M.2; Droin, N.7; Algrin, C.8; Leblond, V.4, 5; Eclache, V.9; Gaillard, B.10; Callet-Bauchu, E.6; Muller, M.11; Lefebvre, C.12; Nadal, N.13; Ittel, A.14; Struski, S.15; Collonge-Rame, M.-A.16; Quilichini, B.17; Fert-Ferrer, S.18; Auger, N.19; Radford-Weiss, I.20; Susin, S.1; Bernard, O.21; Nguyen-Khac, F.1, 2

doi: 10.1097/01.HS9.0000565976.28367.0a
Publication Only: Chronic lymphocytic leukemia and related disorders - Biology & translational research

1Centre de Recherche des Cordeliers, Sorbonne Université

2Service d'Hématologie Biologique, Groupe Hospitalier Pitié-Salpêtrière, paris

3Plateforme de Bioinformatique, Institut Gustave Roussy, Villejuif

4Sorbonne Université

5Service d'Hématologie Clinique, Groupe Hospitalier Pitié-Salpêtrière, Paris

6Service d'Hématologie Biologique, hospices Civils de Lyon, Lyon

7Institut Gustave Roussy, Villejuif

8Service d'Oncologie, Groupe Hospitalier Mutualiste de Grenoble, Grenoble

9Laboratoire d'Hématologie, Hôpital Avicenne, Bobigny

10Hôpital Robert Debré, Reims

11Laboratoire de Génétique, CHU Nancy, Nancy

12Laboratoire de Cytogénétique Onco-hématologique, CHU Grenoble, Grenoble

13Service de génétique chromosomique et moléculaire, CHU Dijon, Dijon

14Laboratoire de Biopathologie, Institut Paoli Calmette, Marseille

15Institut Universitaire du Cancer de Toulouse, Toulouse

16Service de Génétique Biologique-Histologie, CHU Besançon, Besançon

17Département Hématologie Cellulaire/Cytogénétique, Biomnis, Lyon

18Centre Hospitalier Métropole Savoie, Chambéry

19Laboratoire de Cytogénétique, Institut Gustave Roussy, Villejuif

20Laboratoire de Cytogénétique, Hôpital Necker-Enfants Malades, Paris

21INSERM, U1170, Institut Gustave Roussy, Villejuif, France

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B-PLL is a rare entity that was debated. It is now recognized in the WHO classification and defined by the presence of prolymphocytes in peripheral blood (PB) exceeding 55% of lymphoid cells, different from transformed chronic lymphocytic leukemia (CLL) and cases with translocation t(11;14) that are classified as MCL. We previously showed that B-PLL have a high frequency of MYC activation by translocation [t(MYC)] or gain, and frequent del17p, patients with both abnormalities (abs) having the worst prognosis. It has been suggested that B-PLL should be considered as a subgroup of MCL.

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In order to evaluate the relationship between B-PLL and MCL, we compared cytogenetics and molecular data.

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We studied 35 B-PLL and 4 pMCL (≥55% of prolymphocytes in PB) (multicentric study by the Groupe Francophone de Cytogénétique Hématologique and the FILO group), 24 MCL and 16 CLL as control, using karyotype (K), FISH, whole-exome sequencing (WES), IGHV and RNA-sequencing. All MCL had a t(11;14), while the presence of a CCND1, CCND2 or CCND3 rearrangement was excluded in B-PLL cases.

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A morphological review, performed by 3 independent experts, did not show any distinctive features between B-PLL and pMCL. In B-PLL, we found a complex K (CK) (≥3 abs) in 71%, and a highly complex K (HCK ≥ 5) in 44%. The most frequent chromosomal abs were: MYC abs (n = 27, 77%): t(MYC) (n = 22, 63%) or MYC gain (n = 5, 14%) and del17p (n = 13, 37%). Among the 19/24 MCL with an informative K, we found CK in 13 (68%), including 11 HCK (58%) and del11q (ATM) in 3 (16%). By FISH, we found 9 (38%) del17p and 7 (29%) MYC abs (6 gains and 1 t(MYC)). All 4 pMCL had a CK, including 3 HCK, 2 had a t(MYC), 1 a MYC gain, 2 a del17p and 2 a del11q (Figure A). Using WES on 23 B-PLL, the most frequent mutated genes were TP53 (n = 12, 52%), MYC, BCOR (n = 5, 22% each), SETD2, MYD88 (n = 4, 17% each), SF3B1 and CHD2 (n = 3, 13% each). WES performed on 3 pMCL showed 2 cases ATMmut, and 1 CCND1mut/TP53mut (Figure B). Overall, ATM inactivation was present in 1/35 (2.9%) B-PLL vs 3/4 (75%) pMCL (p = .001). The majority of B-PLL used a VH3 or VH4 gene (17/19, 89%), but none of the 4 pMCL (VH1, n = 3, VH2, n = 1). The level of somatic hypermutation was higher in B-PLL: 16/19 (84%) had ≤98% of homology vs 1/4 pMCL (p = .04). Principal component analysis of gene expression data in 12 B-PLL, 3 pMCL and 16 CLL analyzed by RNA-Seq showed that B-PLL and pMCL clustered together, distinctively from CLL (Figure C). However, 386 genes were differently expressed between B-PLL and pMCL, with enrichment in cell cycle genes in pMCL, including CCND1 and CCND2. The level of SOX11 expression was significantly lower in B-PLL than in pMCL (p = .02). Comparing B-PLL and CLL, GSEA analysis revealed enrichment in MYC signaling pathway, and cell metabolism signatures in B-PLL.



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In conclusion, our results show that B-PLL have a genomic profile distinct from MCL and CLL, with frequent t(MYC), TP53, MYC and BCOR mutations. However, B-PLL have similarities with the rare subgroup of pMCL: morphology, high frequency of MYC abs and gene expression profiles related to cell cycle and proliferation. Nevertheless, we highlighted distinctive features in addition to t(11;14): IGHV repertoire and mutation level, SOX11 expression and frequency of ATM abs. Our data advocate that pMCL could be an aggressive form of MCL, which have to be definitely distinguished from B-PLL with a routine test, the karyotype.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.