Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis

Florian Renosi (1) , Anne Roggy (2) , Ambre Giguelay (3, 4, 5) , Lou Soret (1) , Pierre-Julien Viailly (6) , Meyling Cheok (7) , Sabeha Biichle (1) , Fanny Angelot-Delettre (1, 8, 9) , Vahid Asnafi (10) , Elizabeth Macintyre (10) , Sandrine Geffroy (7, 11) , Mary Callanan (12, 13) , Tony Petrella (14, 15) , Eric Deconinck (1) , Etienne Daguindau (1) , Véronique Harrivel (16) , Sabrina Bouyer (17) , Véronique Salaün (18) , Pascale Saussoy (19) , Jean Feuillard (20) , Pascal Fuseau (21) , Philippe Saas (1) , Olivier Adotévi (1) , Fabrice Jardin (4, 5) , Christophe Ferrand (1, 22) , Claude Preudhomme (7, 11) , Jacques Colinge (3, 4, 23) , Christophe Roumier (7, 24) , Francine Garnache-Ottou (1, 22)

1 RIGHT - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
2 EFS BFC (site de Dijon) - Etablissement Français du Sang de Bourgogne Franche-Comté (site de Dijon)
3 ICM - Institut régional de Cancérologie de Montpellier
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
6 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
7 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
8 LabEx LipSTIC - Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer
9 EFS BFC (site de Chalon-sur-Saône) - Etablissement Français du Sang de Bourgogne Franche-Comté (site de Chalon-sur-Saône)
10 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
11 Institut de Pathologie [CHU Lille]
12 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
13 Equipe CADIR (LNC - U1231)
14 UQAM - Université du Québec à Montréal = University of Québec in Montréal
15 Hôpital Maisonneuve-Rosemont
16 CHU Amiens-Picardie
17 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
18 CHU Caen
19 Cliniques universitaires St Luc [Bruxelles]
20 Hôpital Dupuytren [CHU Limoges]
21 CHU de la Martinique [Fort de France]
22 EFS BFC - Etablissement français du sang [Bourgogne-Franche-Comté]
23 UM - Université de Montpellier
24 Service de pathologie [CHU Lille]

Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.

Mots clés: Blastic plasmacytoid dendritic cell neoplasm; Growth; Heterogeneity; Tumorigenesis; Burkitt's lymphoma; Dendritic cell neoplasms; Leukemia; b-cell; Acute; genes; Mutation; Blastic plasmacytoid dendritic cell neoplasm

Domaines: Hématologie; Sciences du Vivant [q-bio]

Florian Renosi, Anne Roggy, Ambre Giguelay, Lou Soret, Pierre-Julien Viailly, et al.. Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis. Blood Advances, 2021, 5 (5), pp.1540-1551. ⟨10.1182/bloodadvances.2020003359⟩. ⟨hal-04210054⟩