SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations.

Chronic myeloid malignancies are categorized to the three main categories myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs) and MDS/MPN overlap. So far, no specific genetic alteration profiles have been identified in the MDS/MPN overlap category. Recent studies identified mutations in SET-binding protein 1 (SETBP1) as novel marker in myeloid malignancies, especially in atypical chronic myeloid leukemia (aCML) and related diseases. We analyzed SETBP1 in 1 130 patients with MPN and MDS/MPN overlap and found mutation frequencies of 3.8% and 9.4%, respectively. In particular, there was a high frequency of SETBP1 mutation in aCML (19/60; 31.7%) and MDS/MPN unclassifiable (MDS/MPN, U; 20/240; 9.3%). SETBP1 mutated (SETBP1mut) patients showed significantly higher white blood cell counts and lower platelet counts and hemoglobin levels than SETBP1 wild-type patients. Cytomorphologic evaluation revealed a more dysplastic phenotype in SETBP1mut cases as compared with wild-type cases. We confirm a significant association of SETBP1mut with -7 and isochromosome i(17)(q10). Moreover, SETBP1mut were strongly associated with ASXL1 and CBL mutations (P<0.001 for both) and were mutually exclusive of JAK2 and TET2 mutations. In conclusion, SETBP1mut add an important new diagnostic marker for MDS/MPN and in particular for aCML.