title: A pathway-based gene signature correlates with therapeutic response in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
abstract: Biomarkers to predict response to therapy in adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are not yet established. In this study, we performed a meta-analysis of earlier genome-wide gene expression studies to identify pathway-based genes that are associated with therapeutic response. The predictive power of these genes was validated by transcript profiling in diagnostic bone marrow samples from Ph+ ALL patients using a quantitative real-time PCR array. Gene expression was correlated with cytogenetic and molecular characteristics, including presence of ABL1 mutations and IKZF1 deletion. A total of 43 de novo Ph+ ALL patients treated uniformly with tyrosine kinase inhibitors combined with chemotherapy were selected to validate 46 identified genes. A 9-gene signature was established to distinguish optimal responders from patients with persistent residual disease and early molecular recurrence. The signature was subsequently validated with 87% predictive accuracy in an independent validation set of patients. When initially optimal responders relapsed, their gene expression patterns also shifted. Optimal responders showed upregulation of genes involved in proliferation and apoptosis pathways, whereas poor responders had higher expression of genes that facilitate tumor cell survival in hypoxic conditions as well as development of drug resistance. This unique 9-gene signature may better enable stratification of patients to proper therapeutic regimens and provides new insights into mechanisms of Ph+ ALL response to therapy.
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Zhuang
authors: Z
authors: Zuo
authors: Dan
authors: D
authors: Jones
authors: Hui
authors: H
authors: Yao
authors: Deborah A
authors: DA
authors: Thomas
authors: Susan
authors: S
authors: O'Brien
authors: Farhad
authors: F
authors: Ravandi
authors: Hagop M
authors: HM
authors: Kantarjian
authors: Lynne V
authors: LV
authors: Abruzzo
authors: L Jeffrey
authors: LJ
authors: Medeiros
authors: Su S
authors: SS
authors: Chen
authors: Rajyalakshmi
authors: R
authors: Luthra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D016000:Cluster Analysis; D020732:Cytogenetic Analysis; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D016313:Genes, abl; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D011237:Predictive Value of Tests; D025341:Principal Component Analysis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C497239:IKZF1 protein, human; D047428:Protein Kinase Inhibitors; D051740:Ikaros Transcription Factor; D011505:Protein-Tyrosine Kinases