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The molecular genetics of chronic neutrophilic leukaemia: defining a new era in diagnosis and therapy

Elliott, Michelle A.a,b; Tefferi, Ayalewa

Current Opinion in Hematology: March 2014 - Volume 21 - Issue 2 - p 148–154
doi: 10.1097/MOH.0000000000000014
MYELOID DISEASE: Edited by Martin S. Tallman

Purpose of review In the current WHO classification of myeloid disorders, chronic neutrophilic leukaemia (CNL) is recognized as a myeloproliferative neoplasm characterized by sustained neutrophilic leukocytosis, hepatosplenomegaly and bone marrow granulocytic hyperplasia without evidence of dysplasia, BCR-ABL1 or rearrangements of PDGFRA, PDGFRB or FGFR1. This diagnosis is contingent upon exclusion of underlying causes of reactive neutrophilia particularly if evidence of myeloid clonality is lacking. The lack of a specific molecular marker has left the diagnosis to be largely one of exclusion. Recently, the molecular landscape shifted with the discovery of specific oncogenic mutations in the colony-stimulating factor 3 receptor gene (CSF3R) in CNL patients. We review the implications for diagnosis, pathogenesis and potential for new therapeutic options.

Recent findings In 2013, oncogenic mutations in CSF3R were identified in a majority of patients with CNL and demonstrated that their downstream signalling was sensitive to known kinase inhibitors. This discovery was then validated with the demonstration of 100% CSF3R mutational frequency (predominately CSF3RT618I) in strictly WHO-defined CNL. Simultaneously, novel somatic mutations in SETBP1 were found to be enriched in CNL with possible prognostic significance.

Summary CNL appears to be driven by specific somatic activating CSF3R mutations. These bestow susceptibility to known kinase inhibitors, opening the door to novel specific therapeutic options for CNL. The diagnosis of CNL will no longer be one only of exclusion, and revision of the current WHO diagnostic criteria is expected to include the molecular criterion of CSF3R mutation positivity.

aDepartment of Internal Medicine, Division of Hematology

bDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

Correspondence to Michelle A. Elliott, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. Tel: +1 507 284 2868; fax: +1 507 266 4972; e-mail:

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins