Abstract 2993: Patterns of recurrent mutations in SETBP1 mutated and wild-type atypical Chronic Myeloid Leukemia patients.
Authors: Redaelli Sara , Valletta Simona , Piazza Rocco , Winkelmann Nils , Spinelli Roberta , Pirola Alessandra , Antolini Laura , Mologni Luca , Donadoni Carla , Papaemmanuil Elli , Schnittger Susanne , Dong-Wook Kim , Boultwood Jacqueline , Rossi Fabio , Gaipa Giuseppe , De Martini Greta , Francia di Celle Paola , Jang Hyun Gyung , Fantin Valeria , Bignell Graham R. , Magistroni Vera , Haferlach Torsten , Pogliani Enrico Maria , Campbell Peter , Chase Andrew J. , Tapper William J. , Cross Nick C.P. , Gambacorti Passerini Carlo 
Published: August 2014

Abstract
Atypical Chronic Myeloid Leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. The molecular pathogenesis of this disease is still unclear and the outcome is poor with no improvement over the last 20 years.
We applied whole exome sequencing approach in 9 aCML patient samples in order to identify possible recurrent alterations. The analysis revealed the presence of unique mutations in 70 genes with 3 cases of SETBP1 alterations.
Some of the genes identified as mutated in the initial set of 9 patients (IDH2, MTA2, EPHB3, ETNK1, GATA2, IRAK4) and having a score higher than 1 in the oncogenic GeneRanker database were resequenced in a cohort of 40 aCML patients (15 with and 25 without SETBP1 mutations). With the exception of IDH2, no other gene was found mutated in any case apart from the index patient.
Evaluation on a larger cohort of 70 aCML samples revealed recurrent SETBP1 mutations in 24.3% of cases (see designated abstract).
To test the relationship between SETBP1 variants and mutations in oncogenes known to be involved in myeloid malignancies, mutations in ASXL1, CBL, CEBPA, DNMT3A, EED, EZH2, FLT3, IDH1/2, JAK2, JARID2, NPM1, N/KRAS, RBBP4, RUNX1, SF3B1, SUZ12, TET2 and WT1 were evaluated in a population of 61 aCML patients (14 with and 47 without SETBP1 mutations) by Sanger sequencing.
Overall we identified 60 mutations in 14 genes: 28 were missense point mutations, 13 nonsense point mutations, 15 missense ins/del and 4 ins/del leading to a premature stop codon. No mutations were found in IDH1, RBBP4, NPM1, JAK2, FLT3, DNMT3A.
Mutations in ASXL1 were present in 14 patients and appeared more frequent in patients with mutated SETBP1 (36% vs 19%) while the 15 TET2 mutations were more prevalent in patients with SETBP1 WT than in mutated samples(28% vs. 14%). Further associations will be presented at the meeting, although further analysis on larger cohorts of patients will be necessary to determine the significance of this differences. Additional data on epigenetic signature of aCML will clarify the role of epigenetic dysregulation in aCML and related diseases.
Citation Format: Sara Redaelli, Simona Valletta, Rocco Piazza, Nils Winkelmann, Roberta Spinelli, Alessandra Pirola, Laura Antolini, Luca Mologni, Carla Donadoni, Elli Papaemmanuil, Susanne Schnittger, Kim Dong-Wook, Jacqueline Boultwood, Fabio Rossi, Giuseppe Gaipa, Greta De Martini, Paola Francia di Celle, Hyun Gyung Jang, Valeria Fantin, Graham R. Bignell, Vera Magistroni, Torsten Haferlach, Enrico Maria Pogliani, Peter Campbell, Andrew J. Chase, William J. Tapper, Nick C.P. Cross, Carlo Gambacorti Passerini. Patterns of recurrent mutations in SETBP1 mutated and wild-type atypical Chronic Myeloid Leukemia patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2993. doi:10.1158/1538-7445.AM2013-2993