A pathway-based gene signature correlates with therapeutic response in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
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.
Zuo
Zhuang
Z
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jones
Dan
D
Yao
Hui
H
Thomas
Deborah A
DA
O'Brien
Susan
S
Ravandi
Farhad
F
Kantarjian
Hagop M
HM
Abruzzo
Lynne V
LV
Medeiros
L Jeffrey
LJ
Chen
Su S
SS
Luthra
Rajyalakshmi
R
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
C497239:IKZF1 protein, human; D047428:Protein Kinase Inhibitors; D051740:Ikaros Transcription Factor; D011505:Protein-Tyrosine Kinases