title: The identification and characterization of a STAT5 gene signature in hematologic malignancies.
abstract: BACKGROUND
  The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies.
  
  
  OBJECTIVE
  Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors.
  
  
  METHODS
  We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes.
  
  
  RESULTS
  Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment.
  
  
  CONCLUSIONS
  The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sonkin
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Xianhui
authors.initials: X
authors.lastname: Rong
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Horrigan
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Regnier
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
authors.forename: Christie
authors.initials: C
authors.lastname: Fanton
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA, USA.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Pinzon-Ortiz
authors.affiliation: Novartis Oncology Global Development, Cambridge, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.affiliation: Novartis Oncology Global Development, Cambridge, MA, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Sirulnik
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morrissey
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Z Alexander
authors.initials: ZA
authors.lastname: Cao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009570:Nitriles; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C540383:ruxolitinib; D053612:Janus Kinases
keywords: JAK-STAT; Ruxolitinib; gene signature; pSTAT5