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A Pathway-Based Gene Signature Correlates with Therapeutic Response in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

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A Pathway-Based Gene Signature Correlates with Therapeutic Response in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Modern Pathology (2010) 23, 1524–1534 1524 & 2010 USCAP, Inc. All rights reserved 0893-3952/10 $32.00 A pathway-based gene signature correlates with therapeutic response in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia Zhuang Zuo1, Dan Jones1, Hui Yao2, Deborah A Thomas3, Susan O’Brien3, Farhad Ravandi3, Hagop M Kantarjian3, Lynne V Abruzzo1, L Jeffrey Medeiros1, Su S Chen1 and Rajyalakshmi Luthra1 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Biomarkers to predict response to therapy in adults with Philadelphia chromosome-positive (Ph þ ) 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 þ 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 þ 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 þ ALL response to therapy. Modern Pathology (2010) 23, 1524–1534; doi:10.1038/modpathol.2010.137; published online 20 August 2010 Keywords: acute lymphoblastic leukemia; gene expression; Philadelphia chromosome; therapeutic response; tyrosine kinase inhibitor Philadelphia chromosome-positive (Ph þ ) acute ALL.1 Approximately one-third of ALL cases afflict lymphoblastic leukemia (ALL) is characterized by adults, therefore there are o600 newly diagnosed the presence of t(9;22)(q34;q11) that results in the adult Ph þ ALL cases each year in the United creation of the BCR–ABL1 fusion protein. Ph þ ALL States.2 Ph þ ALL has a poor prognosis in both accounts for up to 30% of adult and 3% of pediatric children and adults compared with other ALL types. Chemotherapy alone can achieve complete remis- sion (CR) in 50% of these patients compared with 1 Correspondence: Professor R Luthra, PhD, Department of Hema- 80–90% of patients with PhÀ ALL. As a result, topathology, The University of Texas MD Anderson Cancer stem cell transplantation (SCT) in first CR has Center, 8515 Fannin Street, NAO1.061a, Houston, TX 77054, become the standard strategy in treating adult Ph þ USA. ALL patients. With the introduction of tyrosine E-mail: [email protected] Received 8 March 2010; revised 28 June 2010; accepted 28 June kinase inhibitors (TKI), such as imatinib, the CR rate 2010; published online 20 August 2010 has increased significantly, but 30% of the patients www.modernpathology.org Predictive 9-gene signature in adult Ph þ ALL Z Zuo et al 1525 relapse in a short time interval. The 5-year overall high-dose cytarabine and methotrexate) plus either survival (OS) also has remained low, ranging from imatinib or dasatinib.12 We reviewed patient records 5% (465 years old) to 30% (20–44 years old).3 and excluded those patients who had history of Identification of predictive and prognostic factors CML or acute biphenotypic leukemia. Patients who for patient stratification is therefore of crucial did not have adequate RNA from diagnostic bone importance in management. Owing to the rarity marrow (BM) aspirates were also excluded. As a and rapid progression of this disease, however, second phase to this study, additional smaller group relatively few studies related to therapeutic re- of patients seen at our institution from 1 May 2008 sponse and prognostic factors in adults with Ph þ to 31 January 2009 was selected based on the same ALL have been published.4,5 Most of the available criteria to serve as an independent validation set. information is scattered in studies of ALL of all The study was performed according to an approved types.1 Moreover, as Ph þ ALL can be derived from laboratory protocol and in accordance with the blast phase of chronic myelogenous leukemia (CML) Declaration of Helsinki. or biphenotypic leukemia, and the inclusion criteria The diagnostic workup on all patients included a of some earlier studies are unclear, some of the complete blood count, BM aspiration and biopsy, published data are not easily interpreted. Never- conventional cytogenetic analysis (Giemsa-banded theless, these results imply that Ph þ ALL may be karyotype), fluorescence in situ hybridization a heterogeneous group of diseases with different (FISH) using a dual-fusion BCR–ABL1 probe,13 and clinical course and response to therapy. quantitative reverse transcription polymerase chain To further explore the nature of this heterogeneity reaction (qRT-PCR) for BCR–ABL1 fusion transcript at the molecular level, genomic and gene expression levels, as described previously.14,15 Complete mole- profiling studies have been performed in very small cular response (CMR) was signified by undetectable cohorts of adult Ph þ ALL patients, or in mixed levels of BCR–ABL1 transcripts (representing at cohorts of patients with other types of ALL.6–10 least 4.5-log reduction from baseline levels).15 Except for the common finding that most Ph þ ALL ABL1 kinase domain (KD) mutations were assessed cases have deletions on chromosome 7p spanning in relapsed patients using a nested PCR strategy the IKZF1 gene,11 the gene expression profiling covering codons 221 to 500 and a screening strategy results have varied considerably in different studies, as previously described.13,16 and have been of limited clinical utility. The goal of this study was to identify a robust gene signature that predicts therapeutic response in adult Selection of Genes for Transcript Profiling Ph þ ALL patients. We initially selected adults Genes for the test panel were selected by data with de novo Ph þ ALL in our files for this study, all mining and network analysis.17,18 Briefly, gene exp- of whom were uniformly treated with a TKI and ression profiling data from previous studies7–10,19,20 combination chemotherapy. Following our review of comparing therapeutic response with various rea- earlier studies, we selected a representative set gents in ALL patients were pooled and normalized. of genes that enabled us to globally assess the activ- Relative expression levels were calculated, and ities of disease-related pathways. We examined associated with outcomes by analysis of variance a broad spectrum of factors, including clinical (ANOVA). The top associated genes were mapped to characteristics, cytogenetic data, and gene muta- gene ontology (GO) pathways (www.geneontology. tions to correlate with the gene expression profile to org). The GO classifications of interest in this illustrate a thorough picture of the gene effects. Our study included: cell growth and proliferation, cell findings suggest that Ph þ ALL is a heterogeneous communication, metabolism and development, group of diseases with significantly different patho- cell motility, response to stress, and cell death. genesis, clinical manifestations, therapeutic res- Final selection was based on network analysis of ponse, and survival. The gene signature we report the pathways using Ingenuity Pathway Analysis can accurately predict patient response to therapy, software (Ingenuity, Redwood City, CA, USA), in enabling better stratification of patients for assign- combination with expert knowledge of the disease ment to optimal therapeutic regimens. mechanism. Forty-six target genes were selected for profiling study. Gene symbols and their full names Materials and methods are listed in Supplementary Table 1. Patient Selection Transcript Profiling by Low-Density Quantitative The study group included previously untreated PCR Array adults with de novo Ph þ ALL who came to our institution between 1 September 2001 and 30 June Expression profiling of the selected genes was per- 2008. No patient had received previous therapy and formed on BM samples. We used a custom-designed all were treated with the HyperCVAD regimen TaqMan qRT-PCR array, which is a 384-well micro- (hyperfractionated cyclophosphamide, vincristine, fluidic card containing gene-specific forward and doxorubicin, and dexamethasone, alternating with reverse primers and fluorescence-labeled probe in Modern Pathology (2010) 23, 1524–1534 Predictive 9-gene signature in adult Ph þ ALL 1526 Z Zuo et al each well (Applied Biosystems, Foster City, CA, The median follow-up time was 16 months. All USA). Total RNA was extracted from BM
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