ATYPICAL CML GENETICS 

Activating mutations in a specific gene occur in more than 50% of patients with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (CML).

The mutations occur in the CSF3R gene, which encodes the receptor for colony-stimulating factor 3.

These mutations segregate within 2 distinct regions of CSF3R, note the authors, led by Julia E. Maxson, PhD, from the Oregon Health and Science University Knight Cancer Institute in Portland. This leads to preferential downstream kinase signaling through TNK2 or JAK kinases and differential sensitivity to kinase inhibitors, they point out.

The study appears in the May 9 issue of the New England Journal of Medicine.

CNL and atypical (BCR-ABL1-negative) CML are rare cancers; they are so uncommon that their incidence cannot be estimated, writes Jerald Radich, MD, from the Fred Hutchinson Cancer Center in Seattle, Washington, in an accompanying editorial.

Both are characterized by leukocytosis and hypercellular bone marrow in the absence of known mutations; even with standard treatment, the prognosis is dismal, he notes. Median survival is 2 to 3 years, and death usually results from infection and bleeding.

In addition to the possible therapeutic benefit that comes with uncovering these mutations, this study "is important in a broader sense," Dr. Radich says. "It shows the power of genetic screening to uncover new potential drug targets and provide a rationale for using drugs that are already available for other indications."

"Notably, the association between the CSF3R mutation and CNL and atypical CML was found in a large sequencing of the 'usual suspects' of cancer signaling," he writes. "Skeptics often deride large-scale screening studies as fishing expeditions, although these are actually an excellent idea if the object is to catch fish."

Dr. Radich notes that this shows the potential power of studying a small problem "very craftily," and it serves as an example of what genetically informed treatment might look like in the near future. "This is how we will beat cancer, one gene, one disease at a time," he concludes.

Defining Molecular Abnormality

Dr. Maxson and colleagues used an integrated approach of deep sequencing and screening primary leukemia cells obtained from patients with CNL or atypical CML. When possible, they also screened the cells against panels of tyrosine-kinase-specific small interfering RNA or small-molecule kinase inhibitors.

The candidate oncogenes were validated using in vitro transformation assays, and drug sensitivities were validated with assays of primary-cell colonies.

The authors found "enrichment of mutations in CSF3R" in 16 of 27 patients (59%) with CNL or atypical CML. The mutation appears to be primarily limited to CNL and atypical CML; it was rare in other blood cancers.

For example, they identified a CSF3R mutation in 1 of 92 patients with acute myeloid leukemia (AML), and found a low incidence of the mutation (1%) in 2 of 200 patients in the Cancer Genome Atlas AML dataset.

They also found a CSF3R membrane-proximal mutation (T618I) in 1 of 3 patients with early T-cell precursor T-cell acute lymphoblastic leukemia, but not in any of the 8 patients with T-cell acute lymphoblastic leukemia (ALL) or the 41 with B-cell ALL. There were also no CSF3R mutations in 3 patients with reactive neutrophilia.

"Taken together, these data suggest that mutations in CSF3R are a defining molecular abnormality of CNL and atypical CML, and testing for CSF3R mutations could aid in the diagnosis of these diseases," they write. "The CSF3R mutations represent a biologically unifying feature of CNL and atypical CML and define a new molecular subset of hematologic cancers."

The authors add that incorporating CSF3R mutational status into the current diagnostic criteria for CNL and atypical CML could "help refine the molecular classification of myeloproliferative neoplasms and myeloproliferative/myelodysplastic overlap neoplasms."

The study was supported in part by grants from the Leukemia and Lymphoma Society; the Training Program in Molecular Hematology; the National Cancer Institute; the National Center for Advancing Translational Sciences; the National Heart, Lung, and Blood Institute; the St. Baldricks Foundation; the V Foundation for Cancer Research; Gabrielle's Angel Foundation for Cancer Research; and the William Lawrence and Blanche Hughes Fund. Coauthor Brian Druker, MD, is an investigator of the Howard Hughes Medical Institute. Coauthor Michael Deininger, MD, PhD, is a Scholar in Clinical Research of the Leukemia and Lymphoma Society.

N Engl J Med. 2013;368:1781-1790, 1838-1839. Abstract, Editorial