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Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid LeukemiaAndrew J. Gentles, PhD; Sylvia K. Plevritis, PhD; Ravindra Majeti, MD, PhD; Ash A. Alizadeh, MD, PhD3 X6 @% t# C7 r. }" A
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Author Affiliations: Department of Radiology, Lucas Center for MR Spectroscopy and Imaging (Drs Gentles and Plevritis), and Department of Internal Medicine, Divisions of Oncology (Dr Alizadeh) and Hematology (Drs Majeti and Alizadeh), Cancer Center and Institute for Stem Cell Biology and Regenerative Medicine (Drs Majeti and Alizadeh), School of Medicine, Stanford University, Palo Alto, California. 9 u' p' M% w" J, E' V
AbstractContext In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined. 3 f( B4 ~# ^- i( k% E
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Objective To identify an LSC gene expression signature and test its association with clinical outcomes in AML.
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% d$ i/ b' t! ~& F) w8 oDesign, Setting, and Patients Retrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n = 1047).
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! i, W0 @& F1 _Main Outcome Measures Identification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSC-specific genes with overall, event-free, and relapse-free survival and with therapeutic response.
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Results Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n = 163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.08-1.22; log-likelihood P <.001). The absolute risk of death by 3 years was 57% (95% CI, 43%-67%) for the low LSC score group compared with 78% (95% CI, 66%-86%) for the high LSC score group (HR, 1.9 [95% CI, 1.3-2.7]; log-rank P = .002). In another cohort with available data on event-free survival for 70 patients with normal karyotypes, the risk of an event by 3 years was 48% (95% CI, 27%-63%) in the low LSC score group vs 81% (95% CI, 60%-91%) in the high LSC score group (HR, 2.4 [95% CI, 1.3-4.5]; log-rank P = .006). In multivariate Cox regression including age, mutations in FLT3 and NPM1, and cytogenetic abnormalities, the HRs for LSC score in the 3 cohorts with data on all variables were 1.07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005).
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" \$ O3 e5 x3 T+ K* bConclusion High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML. " G4 X$ ]7 F9 k5 U
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KEYWORDS: GENE EXPRESSION, GENETIC PREDISPOSITION TO DISEASE, HEMATOPOIETIC STEM CELLS, LEUKEMIA, MYELOID, ACUTE, MYELOID PROGENITOR CELLS, NEOPLASTIC STEM CELLS, OUTCOME ASSESSMENT (HEALTH CARE). |
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发表于 2010-12-23 12:42
发表于 2010-12-23 14:45
发表于 2011-2-23 16:04
