SETBP1 and CSF3R Mutations In Atypical Chronic Myeloid Leukemia

Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. In aCML many clinical features suggest the diagnosis of CML, however the lack of the BCR-ABL1 fusion point to a different pathogenetic process.

Recently, we identified the presence of clonal somatic mutations occurring in the SETBP1 gene in approximately 25% of aCML samples (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). A subsequent study (Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90) demonstrated the presence of somatic mutations of the CSF3R gene in Chronic Neutrophilic Leukemia (CNL) and, with lower frequency, in aCML. In a recent follow-up of the first study (Gotlib J. et al., Blood. 2013 Jul 29), the presence of both CSF3R and SETBP1 variants was tested in a cohort of 9 CNL and 20 aCML cases, demonstrating the presence of CSF3R somatic mutations in 40% of the aCML patients. Of these mutations, 20% were membrane, 5% truncating and 15% compound variants. Interestingly, 5% of the aCML patients showed coexistence of CSF3R and SETBP1 mutations, suggesting that variants occurring in these genes are not mutually exclusive.

To gain further insight into the relationship between CSF3R and SETBP1 in aCML, we extended our initial study by analyzing an expanded cohort of 65 aCML plus a total of 230 AML, ALL, CLL, CML, PV, TE, MMM, CMML and MDS cases for the presence of CSF3R and SETBP1 mutations. In line with previous findings (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24; Maxson J. et al., N Engl J Med. 2013 May 9;368(19):1781-90), we found evidence of SETBP1 and/or CSF3R mutations only in MDS/MPN disorders. In aCML we identified a total of 18 (27.7%) mutations occurring in SETBP1 and 8 (12.3%) in the CSF3R gene. A large fraction (94.4 %) of the SETBP1 mutations was clustered in a 14 amino acid stretch that is also mutated in the Schinzel-Giedion syndrome, as previously reported (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Of the 8 CSF3R mutations 5 were membrane proximal (4 T618I and 1 T615A) and 3 were truncating (2 Q776X and 1 Q781X). In 2 aCML samples we detected the coexistence of CSF3R and SETBP1 mutations. In both cases the CSF3R variant was a membrane proximal mutation; CSF3R and SETBP1 mutations were at comparable levels at the time of detection, therefore no conclusion can be drawn about the timing of the two mutational events.

Taken globally these data indicate that somatic mutations occurring in SETBP1 and CSF3R are present in aCML and can coexist. Interestingly, the frequency of the CSF3R mutations in our aCML cohort is largely different from that of Maxson and colleagues (12.3 vs 40%), although the frequency of the combined CSF3R/SETBP1 mutations is similar (3.1 vs 5%): the reasons for this discrepancy are actually unclear. Previously we demonstrated that the presence of SETBP1 mutations in aCML is an independent negative prognostic factor (Piazza R. et al., Nat Genet. 2013 Jan;45(1):18-24). Further studies with larger cohorts will be required to assess the prognostic impact of concurrent SETBP1 and CSF3R mutations.