The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment

Abstract

Although activation of tyrosine kinase pathways is a shared theme among myeloproliferative neoplasms, the pathogenetic basis of chronic neutrophilic leukemia (CNL) has remained elusive. Recently, we identified high-frequency oncogenic mutations in the granulocyte-colony stimulating factor receptor (CSF3R) in CNL and in some patients with atypical chronic myeloid leukemia. Inhibition of Janus kinase 2 or SRC kinase signaling downstream of mutated CSF3R is feasible and should be explored therapeutically. Herein, we discuss the potential impact of these findings for the classification and treatment of these disorders.

Figure 1

Mutations in CSF3R and SETBP1 are common in CNL and aCML. Percentages of CSF3R, SETBP1, and JAK2 V617F mutations in 29 patients with CNL or aCML are shown. CSF3R mutations arise in 2 classes, nonsense or frameshift mutations that truncate the cytoplasmic tail (truncation mutations) and point mutations in the extracellular domain (membrane proximal mutation), and some cases exhibit both classes of mutations on the same allele (compound mutations). These mutations can occur in isolation or in combination with other mutant genes, with 21% of patients having both CSF3R and SETBP1 mutations. One patient exhibited mutations in both CSF3R (G683R) and JAK2 (V617F); however, the clonality of this double mutation could not be established due to limited material, presenting the possibility of polyclonal populations of tumor cells with distinct mutational profiles. The frequencies of each class of CSF3R mutation alone or in combination with SETBP1 or JAK2 are shown for a combined cohort of CNL and aCML (n = 29), the CNL cases only (n = 9), and the aCML cases only (n = 20).

Figure 2

Provisional diagnostic algorithm for neutrophilia and genetically informed treatment options. †FISH probes for myeloid-associated cytogenetic abnormalities can be used to complement standard karyotype analysis to establish the presence of a clonal myeloid disorder. Cytogenetic/FISH or molecular evaluation of rearranged PDGFRA/B, and FGFR1 should also be considered if eosinophilia is present. ‡Testing for JAK2 V617F, infrequently identified in CNL or atypical CML, should also be considered. The list of relevant mutations, including molecular abnormalities in complementary signaling pathways to CSF3R and SETBP1, may expand over time. *For patients who are CSF3R-mutation negative, use of a JAK inhibitor (particularly if JAK2 V617F positive) or SRC kinase inhibitor could be considered since mutations in the same or related signaling pathways may be present.