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1.
Blood ; 116(23): 4874-84, 2010 Dec 02.
Article in English | MEDLINE | ID: mdl-20699438

ABSTRACT

To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.


Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Profiling , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Clinical Trials as Topic , Cluster Analysis , DNA Copy Number Variations , Disease-Free Survival , Genome-Wide Association Study , Humans , Kaplan-Meier Estimate , Multigene Family , Oligonucleotide Array Sequence Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Treatment Outcome
2.
Blood ; 115(7): 1394-405, 2010 Feb 18.
Article in English | MEDLINE | ID: mdl-19880498

ABSTRACT

To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate- (62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retainedindependent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603.


Subject(s)
Genetic Testing/methods , Neoplasm, Residual/genetics , Neoplasm, Residual/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Adolescent , Child , Child, Preschool , Female , Flow Cytometry , Gene Expression Regulation, Leukemic , Genetic Testing/standards , Humans , Ikaros Transcription Factor/genetics , Infant , Janus Kinases/genetics , Kaplan-Meier Estimate , Male , Oligonucleotide Array Sequence Analysis , Predictive Value of Tests , Proportional Hazards Models , Recurrence , Reproducibility of Results , Risk Factors , Treatment Outcome , Young Adult
3.
Blood ; 108(2): 685-96, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16597596

ABSTRACT

To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.


Subject(s)
Gene Expression Profiling , Leukemia, Myeloid/genetics , Acute Disease , Adult , Aged , Aged, 80 and over , Apoptosis/genetics , Cluster Analysis , Disease-Free Survival , Drug Resistance, Multiple/genetics , Female , Humans , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/mortality , Male , Middle Aged , Nuclear Proteins/genetics , Nucleophosmin , Prognosis , Remission Induction , Risk Assessment , Signal Transduction/genetics
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