title: CXC chemokine receptor 4 expression, CXC chemokine receptor 4 activation, and wild-type nucleophosmin are independently associated with unfavorable prognosis in patients with acute myeloid leukemia.
abstract: BACKGROUND
  CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in patients with AML and predicts a favorable prognosis. In vitro studies have suggested that mutant nucleophosmin (NPM) decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways.
  
  
  METHODS
  In a group of 117 untreated adults with AML, we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated CXCR4 (pCXCR4) expression. All cases also were analyzed for NPM1 mutations using polymerase chain reaction-based methods.
  
  
  RESULTS
  CXCR4 expression was detected in 75 patients (64%), and pCXCR4 expression was detected in 31 patients (26%). NPM1 mutations were detected in 63 patients (54%). NPM1 mutations did not correlate with CXCR4 (P = .212) or pCXCR4 (P = .355) expression. The median 5-year overall survival was 27% (95% confidence interval, 19-36), with a median follow-up of 8 months (95% confidence interval, 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematologic disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild-type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival.
  
  
  CONCLUSIONS
  There is no correlation between NPM1 mutations and CXCR4 or pCXCR4 expression, suggesting that the CXCR4 and NPM pathways act independently in adult AML.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: skonople@mdanderson.org.
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.forename: C Cameron
authors.initials: CC
authors.lastname: Yin
authors.forename: E
authors.initials: E
authors.lastname: Lin
authors.forename: Graciela M
authors.initials: GM
authors.lastname: Nogueras González
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D010766:Phosphorylation; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D000090243:Nucleophosmin
keywords: AML; Acute myeloid leukemia; CXCR4; CXCR4 activation; CXCR4 phosphorylation; NPM1; Prognosis
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