Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML

Julia E. Maxson, Jason Gotlib, Daniel A. Pollyea, Angela G. Fleischman, Anupriya Agarwal, Christopher A. Eide, Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, Cristina E. Tognon, J. Blake Pond, Robert H. Collins, Basem Goueli, T. Oh Stephen, W. Deininger Michael, Bill H. Chang, Marc M. Loriaux, Brian J. Druker, Jeffrey W. Tyner

Research output: Contribution to journalArticlepeer-review

429 Scopus citations


BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative- myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.)

Original languageEnglish (US)
Pages (from-to)1781-1790
Number of pages10
JournalNew England Journal of Medicine
Issue number19
StatePublished - 2013

ASJC Scopus subject areas

  • General Medicine


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