Clinical significance of CSF3R, SRSF2 and SETBP1 mutations in chronic neutrophilic leukemia and chronic myelomonocytic leukemia

Abstract

Chronic neutrophilic leukemia (CNL) and chronic myelomonocytic leukemia (CMML) are rare hematologic neoplasms. We performed CSF3R, SRSF2 and SETBP1 mutational analyses in 10 CNL and 56 CMML patients. In this sample cohort, 80% of CNL patients harbored CSF3R mutations, of which the CSF3R T618I mutation was dominant. Mutations in CSF3R and SETBP1 were found in 7.1% and 5.3% CMML patients respectively, while 25% of CMML patients carried SRSF2 mutations. Strikingly, we identified that all of the CSF3R mutations detected in CMML patients were represented by a P733T mutation. The CSF3R P733T mutation represents a novel CSF3R mutation. In addition, none of the four CSF3R P733T mutated patients carried SRSF2 mutations [0/14 (0%) patients with combined CSF3R P733T and SRSF2 mutations vs. 4/42 (9.5%) with CSF3R P733T and wt SRSF2, P < 0.001]. Both mut SRSF2 and mut SETBP1 patients had shorter overall survival (OS) and progression-free survival (PFS) compared to patients with wt SRSF2 (P < 0.001 both) and wt SETBP1 (P < 0.001 and P = 0.02, respectively). While we found no significant differences in OS and PFS as a consequence of CSF3R mutation status, our work suggest that the CSF3R T618I mutation is a diagnostic marker with good specificity and sensitivity for CNL. In conclusion, our study highlights effective diagnostic and prognostic markers of CNL and CMML patients in the Chinese population.

Keywords: CMML; CNL; CSF3R; SRSF2; gene mutation.

Figure 1. Frequency distribution of CSF3R and SRSF2 mutations in CNL and CMML patients

(A) In 10 patients with CNL, 8(8/10, 80%) patients had CSF3R mutation and 7(7/8, 87.5%) of them were with CSF3R T618I. (B) In 56 CMML patients, 14(14/56, 25%) patients were found to have SRSF2 mutations, including P95H, P95L, P95R and P95fs*19.

Figure 2. Frequency distribution of CSF3R, SETBP1 and SRSF2 genetic aberrations in CNL and CMML patients

Each box indicates 1 patient. Dark gray boxes are indicative for patients who are positive for the respective mutation; light gray boxes indicate wild type status.

Figure 3. Kaplan-Meier curves for OS, PFS according to genotypes with statistical significance in univariate analysis

(A–C) Overall survival (OS) for SRSF2, SETBP1 and CSF3R cases. (D–F) Progression-free survival (PFS) for SRSF2, SETBP1 and CSF3R cases. In univariate analysis, SRSF2 and SETBP1 mutations suggested a poor prognosis for OS (P < 0.001both) and PFS (P < 0.001 and P = 0.02, respectively). There was no statistical significance of CSF3R mutations in OS and PFS (P > 0.05).