Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes

Jatinder K. Lamba, Kristine R. Crews, Stanley B. Pounds, Xueyuan Cao, Varsha Gandhi, William Plunkett, Bassem I. Razzouk, Vishal Lamba, Sharyn D. Baker, Susana C. Raimondi, Dario Campana, Ching Hon Pui, James R. Downing, Jeffrey E. Rubnitz, Raul C. Ribeiro

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aim: 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. Materials & 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 5́Ấ-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 LC50. Results: We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤â‰& 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)327-339
Number of pages13
JournalPharmacogenomics
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Cytarabine
Transcriptome
Acute Myeloid Leukemia
Phenotype
Arabinofuranosylcytosine Triphosphate
Pharmacology
Genes
Pharmacogenetics
Residual Neoplasm
G-Protein-Coupled Receptors
Disease-Free Survival
Bone Marrow
Gene Expression
DNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes. / Lamba, Jatinder K.; Crews, Kristine R.; Pounds, Stanley B.; Cao, Xueyuan; Gandhi, Varsha; Plunkett, William; Razzouk, Bassem I.; Lamba, Vishal; Baker, Sharyn D.; Raimondi, Susana C.; Campana, Dario; Pui, Ching Hon; Downing, James R.; Rubnitz, Jeffrey E.; Ribeiro, Raul C.

In: Pharmacogenomics, Vol. 12, No. 3, 01.03.2011, p. 327-339.

Research output: Contribution to journalArticle

Lamba, JK, Crews, KR, Pounds, SB, Cao, X, Gandhi, V, Plunkett, W, Razzouk, BI, Lamba, V, Baker, SD, Raimondi, SC, Campana, D, Pui, CH, Downing, JR, Rubnitz, JE & Ribeiro, RC 2011, 'Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes', Pharmacogenomics, vol. 12, no. 3, pp. 327-339. https://doi.org/10.2217/pgs.10.191
Lamba, Jatinder K. ; Crews, Kristine R. ; Pounds, Stanley B. ; Cao, Xueyuan ; Gandhi, Varsha ; Plunkett, William ; Razzouk, Bassem I. ; Lamba, Vishal ; Baker, Sharyn D. ; Raimondi, Susana C. ; Campana, Dario ; Pui, Ching Hon ; Downing, James R. ; Rubnitz, Jeffrey E. ; Ribeiro, Raul C. / Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes. In: Pharmacogenomics. 2011 ; Vol. 12, No. 3. pp. 327-339.
@article{c1a0157865024a8cab15cf4c5095325d,
title = "Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes",
abstract = "Aim: 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. Materials & 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 5́Ấ-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 LC50. Results: We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤{\^a}‰& 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. Conclusion: 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.",
author = "Lamba, {Jatinder K.} and Crews, {Kristine R.} and Pounds, {Stanley B.} and Xueyuan Cao and Varsha Gandhi and William Plunkett and Razzouk, {Bassem I.} and Vishal Lamba and Baker, {Sharyn D.} and Raimondi, {Susana C.} and Dario Campana and Pui, {Ching Hon} and Downing, {James R.} and Rubnitz, {Jeffrey E.} and Ribeiro, {Raul C.}",
year = "2011",
month = "3",
day = "1",
doi = "10.2217/pgs.10.191",
language = "English (US)",
volume = "12",
pages = "327--339",
journal = "Pharmacogenomics",
issn = "1462-2416",
publisher = "Future Medicine Ltd.",
number = "3",

}

TY - JOUR

T1 - Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes

AU - Lamba, Jatinder K.

AU - Crews, Kristine R.

AU - Pounds, Stanley B.

AU - Cao, Xueyuan

AU - Gandhi, Varsha

AU - Plunkett, William

AU - Razzouk, Bassem I.

AU - Lamba, Vishal

AU - Baker, Sharyn D.

AU - Raimondi, Susana C.

AU - Campana, Dario

AU - Pui, Ching Hon

AU - Downing, James R.

AU - Rubnitz, Jeffrey E.

AU - Ribeiro, Raul C.

PY - 2011/3/1

Y1 - 2011/3/1

N2 - Aim: 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. Materials & 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 5́Ấ-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 LC50. Results: We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤â‰& 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. Conclusion: 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.

AB - Aim: 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. Materials & 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 5́Ấ-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 LC50. Results: We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤â‰& 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. Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=79953251738&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953251738&partnerID=8YFLogxK

U2 - 10.2217/pgs.10.191

DO - 10.2217/pgs.10.191

M3 - Article

VL - 12

SP - 327

EP - 339

JO - Pharmacogenomics

JF - Pharmacogenomics

SN - 1462-2416

IS - 3

ER -