Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

Atypical chronic myeloid leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. aCML shares clinical and laboratory features with Chronic Myeloid Leukemia (CML), but it lacks the Philadelphia chromosome and the resulting BCR-ABL fusion gene. This crucial difference with CML points to a different pathogenetic process. Because no specific recurrent genomic or karyotypic abnormalities have been identified in aCML, and the molecular pathogenesis of this disease has remained elusive with a dismal outcome, we performed exome-sequencing of eight aCML patients, in order to identify new possible recurrent mutations. The presence of an identical mutation not previously involved in cancer in two different aCML cases altering SETBP1 gene, prompted us to resequence this particular gene in samples from additional subjects with aCML or other hematological malignancies and in cell lines representative of the most common human solid cancers. SETBP1 mutations were identified only in aCML and in the closely related disorders and represents the first gene shown to be enriched and recurrently mutated in aCML. Most SETBP1 mutations were located between codons 858 and 871 causing abrogation of a degron binding site for E3-ubiquitin β-TrCP1 and protection from proteasomal degradation. This causes accumulation of SETBP1 and SET protein, decreased PP2A phosphatase activity and higher proliferation rates. Individuals with SETBP1 mutations had higher white blood cell counts and worse prognosis, indicating SETBP1 as a possible valuable diagnostic tool in the differential diagnosis of MDS/MPN syndromes and their prognosis. This study increases the knowledge of the mechanisms by which malignancy arises and will have important consequences for the diagnosis, prognosis and treatment of aCML and diseases associated with SETBP1 alterations.