Genomics of chronic neutrophilic leukemia

Abstract

Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to include CSF3R mutations as part of the diagnostic criteria for CNL. Because of the high prevalence of CSF3R mutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations in SETBP1, spliceosome proteins (SRSF2, U2AF1), and epigenetic modifiers (TET2, ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition of CSF3R mutations relative to mutations in SETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.

Figure 1.

CSF3R mutations activate kinase signaling to promote the expansion of neutrophils. CSF3R has an N-terminal extracellular domain comprising an Ig-like domain (dark green) and fibronectin type-III repeats (light green). The T618I and T615A (not shown) mutations in the extracellular domain and the T640N mutation in the transmembrane domain (purple) cause ligand-independent receptor activation. Truncation mutations in the cytoplasmic domain (gray) cause increased cell-surface expression of the receptor. CNL-associated mutations in CSF3R cause activation of downstream kinase signaling pathways, such as the JAK/STAT pathway, ultimately driving neutrophil production. P, phosphorylation.

Figure 2.

Mutations in SETBP1 cause protein overexpression and lead to loss of tumor suppressor function and altered myeloid transcription factor expression. CNL-associated mutations in SETBP1 occur in the β-TrCP1 degron motif. β-TrCP1 binding leads to formation of an E3 ligase complex to degrade SETBP1. Mutations in the degron motif therefore lead to SETBP1 overexpression, which can cause stabilization of its binding partner SET, and together they can inhibit the tumor suppressor PP2A. In addition, SETBP1 binds to the RUNX1 promoter and when overexpressed, it recruits the nucleosome remodeling deacetylase (NuRD) complex to the RUNX1 promoter, inhibiting transcription of this important myeloid regulator. AT-hook, DNA-binding motif that prefers AT-rich sequences; SKI, V-Ski avian sarcoma viral oncogene homolog.

Figure 3.

Summary of mutation currently reported to co-occur in CNL and aCML. These include CSF3R, other signaling genes (purple), spliceosome-associated genes (light green), and genes that have an impact on epigenetics and gene transcription (gray).

Figure 4.

Longitudinal acquisition of mutations may have an impact on disease course and therapeutic strategies. Recent genomic findings in CNL and aCML have indicated that mutations may arise in at least 3 different categories of genes: epigenetic modifiers, components of the spliceosome, and growth factor signaling pathways. It is likely that these mutations are acquired through a process of age-related clonal hematopoiesis (Hem) in which 1 of these mutational events initiates (A) a dysplastic or (B) a proliferative anomaly with subsequent acquisition of the other gene categories resulting in evolution to overt disease. The identity of the gene that initiates this process may have important implications for the manner in which the disease proceeds down distinct diagnostic trajectories as well as the possibility for success of targeted therapies such as tyrosine kinase inhibitors (TKIs) as well as emerging agents that target epigenetic or splicing processes.