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.
Highlights
Chronic neutrophilic leukemia (CNL) is a rare hematologic neoplasm that is diagnosed largely based on exclusion of underlying causes of reactive neutrophilia and/or the lack of specific molecular markers of other hematological malignancies [1]
While we found no significant differences in overall survival (OS) and progression-free survival (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
We found that 80% (8/10) of CNL patients harbored CSF3R mutations
Summary
CNL is a rare hematologic neoplasm that is diagnosed largely based on exclusion of underlying causes of reactive neutrophilia and/or the lack of specific molecular markers of other hematological malignancies [1]. Until the recent discoveries of CSF3R and SETBP1 mutations [2], no recurrent genetic abnormalities have been identified in CNL. While CSF3R mutations are most commonly found in severe congenital neutropenia (SCN), the rates of CSF3R mutations rises sharply upon progression to secondary acute myeloid leukemia (sAML) [4,5,6]. CSF3R mutations may critically influence on disease progression to AML, the types of truncation mutations that associate with sAML are rarely detected in other disorders, including de novo AML6. Acquired CSF3R mutations (in particular the CSF3R T618I mutation) were described in a majority of patients diagnosed with CNL or atypical chronic myeloid leukemia (aCML) [2, 7]. Kosmider et al identified about 3% of CMML patients with CSF3R somatic mutations, while Pardanani et al failed to identify CSF3R mutations in CMML [8, 9]
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