Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes

Véronique Gelsi-Boyer (1, 2) , Virginie Trouplin (1, 2) , José Adélaïde (1, 2) , Nicola Aceto (3) , Virginie Remy (1, 2) , Stephane Pinson (4) , Claude Houdayer (5) , Christine Arnoulet (2) , Danielle Sainty (2) , Mohamed Bentires-Alj (3) , Sylviane Olschwang (1, 2) , Norbert Vey (2) , Marie-Joëlle Mozziconacci (1, 2) , Daniel Birnbaum (1, 2) , Max Chaffanet (1, 2)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 IPC - Institut Paoli-Calmettes
3 FMI - Friedrich Miescher Institute for Biomedical Research
4 Hôpital Edouard Herriot [CHU - HCL]
5 Institut Curie [Paris]

Abstract Background Chronic myelomonocytic leukemia (CMML) is a hematological disease close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML) or myelodysplastic (MD-CMML) features. Not much is known about the molecular biology of this disease. Methods We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases) from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH) and sequencing of 12 candidate genes. Results Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q) and gain or loss of genes (e.g. NF1 , RB1 and CDK6 ). RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS ) and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements). The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16 . RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46%) but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement) occurred in both MP and MD classes (~38%). Conclusion We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage.

Domaines: Cancer

Véronique Gelsi-Boyer, Virginie Trouplin, José Adélaïde, Nicola Aceto, Virginie Remy, et al.. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes. BMC Cancer, 2008, 8 (1), pp.299. ⟨10.1186/1471-2407-8-299⟩. ⟨hal-03634388⟩