Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes

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.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%).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.Chronic myelomonocytic leukemia (CMML) is a heterogeneous hematopoietic disease currently classified by the WHO organization as an entity close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes. CMML is included in the category of MPD/MDS diseases and defined by persistent peripheral monocytosis greater than 1 × 109/L, fewer than 20% blasts in the blood or bone marrow (BM), and BM dysplasia in one or more myeloid lineage. Because the blast number is a prognostic factor, CMML is divided in two types: type 1 with fewer than 5% in blood and 10% blasts in BM, and type 2 between 5 and 19% in blood or 10 and 19% in BM [1,2].The problem of CMML resides in its classification and in the clinical and/or biological relevance of separating the proliferative and dysplastic presentations. The FAB