Clinical Significance of CSF3R, SRSF2 and SETBP1 mutation in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia

Objective: To investigate the gene mutation and the clinical features of CSF3R, SETBP1 and SRSF2 in chronic neutrophilic leukemia (CNL) and chronic myelomonocytic leukemia (CMML) patients.

Method: Sequence analysis of CSF3R, SETBP1 and SRSF2 were performed in 10 CNL and 56 CMML patients whose clinical features were also studied.

Result: Among 10 CNL patients, 8(8/10, 80%) patients had CSF3R mutations and 7(7/8, 87.5%) of them were with CSF3R T618I. In 56 cases of patients with CMML, SRSF2 mutations were found in 14(14/56,25%), CSF3R in 4(4/56,7.1%) and SETBP1 in 3(3/56, 5.3%) patients. In CMML, compared to wild-type(wt) SRSF2 patients, SRSF2 mutated patients appeared to be more possible with SETBP1 mutations [1/14(7.1%) vs. 2/42(4.8%), P>0.05], less possible with CSF3R mutation [0/14(0%) vs. 4/42(9.5%), P<0.001]. The clinical characteristics such as age, gender, WHO category, FAB category, karyotype and blood cell counts did not reveal any difference between SRSF2 mutated and wtSRSF2 patients. Either SRSF2 mutated patients or SETBP1 mutated patients both had shorter overall survival (OS) and progression-free survival(PFS) when compared with those with wtSRSF2 (P<0.001 both) and wtSETBP1 (P<0.001 and P=0.02, respectively). No significant difference of OS and PFS between CSF3R mutated and wtCSF3R patients were observed. In multivariate analysis, SRSF2 mutation was an independent negative predictor for OS (HR, 3.307; 95% CI, 1.137 to 9.614; P=0.028) and PFS(HR, 15.431; 95% CI, 3.041 to 78.312; P = 0.001). What's more, SETBP1 mutation was also an independent negative predictor for OS(HR, 9.492; 95% CI, 1.183 to 76.128; P = 0.034).

Conclusion: The majority of patients with WHO-defined CNL have oncogenic mutations in CSF3R and the T618I mutation type is a highly sensitive and specific molecular marker of the disease. While mutations of SRSF2 are common in CMML and may be of prognostic significance. As a non-specific molecular marker, SETBP1 was found in CNL, CMML and other blood cancers, which have poor prognosis.