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

Michelle A. Elliott, Ayalew Tefferi

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)148-154
Number of pages7
JournalCurrent opinion in hematology
Issue number2
StatePublished - Mar 1 2014


  • CSF3RT618I
  • Chronic
  • Colony-stimulating factor 3 receptor gene mutations
  • Leukaemia
  • Neutrophilic

ASJC Scopus subject areas

  • Hematology


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