title: Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes.
abstract: OBJECTIVE
  To identify gene-expression signatures predicting cytarabine response by an integrative analysis of multiple clinical and pharmacological end points in acute myeloid leukemia (AML) patients.
  
  
  METHODS
  We performed an integrated analysis to associate the gene expression of diagnostic bone marrow blasts from acute myeloid leukemia (AML) patients treated in the discovery set (AML97; n = 42) and in the independent validation set (AML02; n = 46) with multiple clinical and pharmacological end points. Based on prior biological knowledge, we defined a gene to show a therapeutically beneficial (detrimental) pattern of association of its expression positively (negatively) correlated with favorable phenotypes such as intracellular cytarabine 5´-triphosphate levels, morphological response and event-free survival, and negatively (positively) correlated with unfavorable end points such as post-cytarabine DNA synthesis levels, minimal residual disease and cytarabine LC(50).
  
  
  RESULTS
  We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤ 0.005) in the discovery set. Of these, 60 were confirmed in the independent validation set. The validated probe sets correspond to genes involved in PIK3/PTEN/AKT/mTOR signaling, G-protein-coupled receptor signaling and leukemogenesis. This suggests that targeting these pathways as potential pharmacogenomic and therapeutic candidates could be useful for improving treatment outcomes in AML.
  
  
  CONCLUSIONS
  This study illustrates the power of integrated data analysis of genomic data as well as multiple clinical and pharmacologic end points in the identification of genes and pathways of biological relevance.
authors: Department of Experimental & Clinical Pharmacology, University of Minnesota, MN, USA. lamba004@umn.edu
authors: Jatinder K
authors: JK
authors: Lamba
authors: Kristine R
authors: KR
authors: Crews
authors: Stanley B
authors: SB
authors: Pounds
authors: Xueyuan
authors: X
authors: Cao
authors: Varsha
authors: V
authors: Gandhi
authors: William
authors: W
authors: Plunkett
authors: Bassem I
authors: BI
authors: Razzouk
authors: Vishal
authors: V
authors: Lamba
authors: Sharyn D
authors: SD
authors: Baker
authors: Susana C
authors: SC
authors: Raimondi
authors: Dario
authors: D
authors: Campana
authors: Ching-Hon
authors: CH
authors: Pui
authors: James R
authors: JR
authors: Downing
authors: Jeffrey E
authors: JE
authors: Rubnitz
authors: Raul C
authors: RC
authors: Ribeiro
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D010641:Phenotype; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine