CSF3R Is Mutated in Chronic Neutrophilic Leukemia and Atypical CML

Chronic neutrophilic leukemia (CNL) and atypical, BCR–ABL-negative chronic myelogenous leukemia (CML) are rare hematologic cancers with no known genetic causes. Without distinguishing molecular features, CNL and atypical CML are diagnosed based on abnormal granulocytic cell expansion and the absence of gene arrangements found in other blood cancers, and treatment has been limited to noncurative cytotoxic therapies. Hypothesizing that CNL and atypical CML may be like other hematologic malignancies and driven by oncogenic mutations that confer sensitivity to small-molecule kinase inhibitors, Maxson and colleagues sequenced the coding regions of over 1,800 kinase, phosphatase, non-kinase receptor, and adapter genes in primary cells from 27 patients with CNL or atypical CML and screened for sensitivity to kinase inhibition. Mutations in colony-stimulating factor 3 receptor (CSF3R) were found in 59% of patients but rarely occurred in other hematologic cancers, indicating that CSF3R mutation may be a diagnostic feature of CNL and atypical CML. CSF3R mutations were transforming in vitro and could be grouped into 2 classes: cytoplasmic tail truncation mutations and plasma membrane-proximal mutations. Truncation mutations led to activation of tyrosine kinase nonreceptor 2 (TNK2) and SRC family kinases (SFK), and primary cells with these mutations were highly sensitive to TNK2/SFK inhibition by the multikinase inhibitor dasatinib. In contrast, membrane-proximal mutations activated JAK–STAT signaling, and cells with these mutations were highly sensitive to the JAK inhibitor ruxolitinib. Of note, a patient with membrane-proximal CSF3R-mutant CNL was treated with ruxolitinib and experienced significant clinical improvement, including decreases in total white cell and absolute neutrophil counts and platelet count normalization. Together, these findings identify CSF3R mutations as a distinguishing feature of CNL and atypical CML and suggest that these cancers may respond to TNK2/SFK or JAK inhibitors.

Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368:1781–90.