Identification of Oncogenic Mutations in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia 


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The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of SRC family–TNK2 and JAK kinases and may provide a new avenue for therapy [in chronic neutrophilic leukemia and atypical chronic myeloid leukemia].

—Julia E. Maxson, PhD, and colleagues

Among the hematologic cancers for which molecular causes remain unclear are chronic neutrophilic leukemia and atypical (BCR-ABL1–negative) chronic myeloid leukemia. Both disorders currently are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic factors known to occur in other myeloproliferative cancers. In a study recently reported in The New England Journal of Medicine, Julia E. Maxson, PhD, of Oregon Health & Science University, Portland, and colleagues identified activating mutations in the gene encoding for colony-stimulating factor 3 receptor (CSF3R) in a majority of patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia.1 Identification of these mutations may prove useful in diagnosis and in suggesting potential treatment strategies.

To identify potential genetic drivers, the investigators used deep-sequencing analysis and screening of primary leukemia cells from chronic neutrophilic leukemia and atypical chronic myeloid leukemia patients against panels of tyrosine kinase–specific small interfering RNAs or small-molecule kinase inhibitors. The candidate oncogenes were validated with in vitro transformation assays, and drug sensitivities were validated using primary cell colony assays.

CSF3R Mutations in 59%

Enrichment of mutations in CSF3R were found in 16 (59%) of 27 patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia. Sequence variants included membrane proximal mutations (T615A and T618I) and several frameshift or nonsense mutations that truncate the cytoplasmic tail of CSF3R (D771fs, S783fs, Y752X, and W791X). The investigators noted that similar mutations that truncate the CSF3R cytoplasmic domain have been found in patients with congenital neutropenia that progresses to acute myeloid leukemia after long-term granulocyte colony-stimulating factor (filgrastim [Neupogen]) treatment. Five of the patients had both membrane proximal and truncation mutations, and it was found that these compound mutations can occur on the same CSF3R allele with no required order of mutation acquisition.

In comparison, CSF3R mutations were found in only 3 (1%) of 292 patients with acute myeloid leukemia (including 2 of 200 in the Cancer Genome Atlas acute myeloid leukemia dataset), 0 of 8 with T-cell acute lymphoblastic leukemia, 1 of 3 with early T-cell precursor T-cell acute lymphoblastic leukemia, and 0 of 41 with B-cell acute lymphoblastic leukemia. As stated by the investigators, “Taken together, these data suggest that mutations in CSF3R are a defining molecular abnormality of [chronic neutrophilic leukemia] and atypical [chronic myeloid leukemia], and testing for CSF3R mutations could aid in the diagnosis of these diseases.”

Characteristics of Two Mutation Types

Analysis of cells from a small number of patients with either truncation mutations or membrane proximal mutations revealed important differences between the two types of mutation with regard to downstream kinase signaling and sensitivity to kinase inhibitors. In particular, it was found that truncation mutations result in dysregulation of SRC family-TNK2 kinases and that membrane proximal mutations result in dysregulation of JAK family kinases. Truncation mutations conferred sensitivity to SRC family-TNK2 inhibition, including sensitivity to the multikinase inhibitor dasatinib (Sprycel) but not to JAK kinase inhibitors, whereas membrane-proximal mutations conferred sensitivity to JAK kinase inhibitors including ruxolitinib (Jakafi) but not to SRC family-TNK2 inhibitors.

Response to Ruxolitinib

Primary cells from a patient with chronic neutrophilic leukemia with a membrane proximal (T618I) CSF3R mutation showed in vitro hypersensitivity to ruxolitinib. Treatment of this patient with oral ruxolitinib at 10 mg twice daily resulted in a marked reduction in white blood cell and absolute neutrophil counts, with an increase in ruxolitinib dose to 15 mg twice daily providing further reductions in both. Treatment concurrently resulted in normalization of the patient’s platelet count.

The investigators concluded, “[T]he presence of CSF3R mutations identified a distinct diagnostic subgroup of more than 50% of patients with [chronic neutrophilic leukemia or atypical chronic myeloid leukemia] in our study. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of SRC family–TNK2 and JAK kinases and may provide a new avenue for therapy.” ■

Disclosure: The study was funded by the Leukemia and Lymphoma Society and others. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Maxson JE, Gotlib J, Pollyea DA, et al: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 368:1781-1790, 2013.


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