title: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML.
abstract: 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.).
authors: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors: Julia E
authors: JE
authors: Maxson
authors: Jason
authors: J
authors: Gotlib
authors: Daniel A
authors: DA
authors: Pollyea
authors: Angela G
authors: AG
authors: Fleischman
authors: Anupriya
authors: A
authors: Agarwal
authors: Christopher A
authors: CA
authors: Eide
authors: Daniel
authors: D
authors: Bottomly
authors: Beth
authors: B
authors: Wilmot
authors: Shannon K
authors: SK
authors: McWeeney
authors: Cristina E
authors: CE
authors: Tognon
authors: J Blake
authors: JB
authors: Pond
authors: Robert H
authors: RH
authors: Collins
authors: Basem
authors: B
authors: Goueli
authors: Stephen T
authors: ST
authors: Oh
authors: Michael W
authors: MW
authors: Deininger
authors: Bill H
authors: BH
authors: Chang
authors: Marc M
authors: MM
authors: Loriaux
authors: Brian J
authors: BJ
authors: Druker
authors: Jeffrey W
authors: JW
authors: Tyner
mesh_terms: D000818:Animals; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D007945:Leukemia, Lymphoid / Q000235:genetics; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000175:diagnosis / Q000235:genetics*; D015467:Leukemia, Neutrophilic, Chronic / Q000175:diagnosis / Q000235:genetics*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C517047:CSF3R protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D016184:Receptors, Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D053612:Janus Kinases
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