title: Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia.
abstract: OBJECTIVE
  By parallel assessment of multiple apoptosis-related transcripts, we aimed to refine the current concept of apoptosis resistance in acute myeloid leukemia (AML) and identify the combination of genes best predicting overall survival (OS).
  
  
  METHODS
  The reverse transcriptase multiplex ligation-dependent probe amplification technique was used for simultaneous quantification of 31 apoptosis-related transcripts in viable (7AAD-/AnnexinV-) blasts (CD45dim) from bone marrow aspirates of 120 newly diagnosed AML patients. By forward selection, a prognosis-predicting gene expression profile was constructed. The predictive validity of this profile was assessed by cross validation.
  
  
  RESULTS
  High transcript levels were associated with poor OS for seven of 31 genes, three of which were proapoptotic. The average expression of all 12 antiapoptotic genes was associated with poor OS (P = .029). A similar association with poor OS was found for the average expression of all 19 proapoptotic genes (P = .009). Forward selection and cross validation revealed the antiapoptotic gene BIRC3 and the proapoptotic genes BAX-(l) and BMF to optimally predict OS. Three equally sized patient groups, constructed by ranking the cross-validated prognoses of the patients, were clearly distinct (median OS times were 8.2, 16.7, and 85.6 months).
  
  
  CONCLUSIONS
  High expression of both pro- and antiapoptotic genes predicted poor OS, which postulates a mechanism of activation of the apoptosis pathway as a whole. This mechanism, which culminates in a three-gene expression signature, allows accurate clinical outcome prediction in AML and puts efforts to target single antiapoptosis genes in a new perspective.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Corine J
authors.initials: CJ
authors.lastname: Hess
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.forename: Fedor
authors.initials: F
authors.lastname: Denkers
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Jan P
authors.initials: JP
authors.lastname: Schouten
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oudejans
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Schuurhuis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D044767:Ubiquitin-Protein Ligases; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; C486655:BMF protein, human; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases