Analysis of CSF3R mutations in atypical chronic myeloid leukemia and other myeloid malignancies.

We report a series of patients with CSF3R-mutant (CSF3Rmut) atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL) or other hematologic malignancies. We included 25 patients: 5 aCML and 4 CNL CSF3Rmut patients; 1 aCML, 2 CNL, and 2 myelodysplastic/myeloproliferative neoplasm, not otherwise specified patients without CSF3R mutation; and 11 CSF3Rmut patients with other diseases [8 acute myeloid leukemia (AML), 1 chronic myelomonocytic leukemia (CMML), 1 myelodysplastic syndrome (MDS), and 1 acute lymphoblastic leukemia (ALL)]. Patients with aCML or CNL were tested by Sanger sequencing and pyrosequencing to identify CSF3R T618I. Twenty-two patients underwent gene panel analysis. CSF3R mutations, mostly T618I (8/9), were found at high frequencies in both aCML and CNL patients [5/6 aCML and 4/6 CNL]. Two aCML patients in early adulthood with CSF3R T618I and biallelic or homozygous CEBPA mutations without other mutations presented with increased blasts and exhibited remission for >6 years after transplantation. The other 7 CSF3Rmut aCML or CNL patients were elderly adults who all had ASXL1 mutations and frequently presented with SEBP1 and SRSF2 mutations. Five AML patients had CSF3R exon 14 or 15 point mutations, and 6 other patients (3 AML, 1 CMML, 1 MDS, and 1 ALL) had truncating mutations, demonstrating differences in leukocyte counts and mutation status. In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia.

CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.