Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia
Authors: Andrew J. Gentles
Journal: JAMA (2010)

CUTE MYELOID LEUKEMIA(AML) is an aggressive malignancy of the bone marrow characterized by accumulation of early myeloid blood cells that fail to mature and differentiate.The course of the disease is marked by poor prognosis, frequent relapse, and high disease-related mortality. 1,2Recent clinical investigation has focused on the identification of prognostic subgroups in adult AML with the goal of guiding patients into risk-adapted therapies.Such investigation determined that cytogenetic abnormalities are prognostic, some favorable and others unfavorable, 3,4 yet up to 50% of patients have normal karyotype AML with a wide range of clinical outcomes.In these patients, the presence of specific molecular mutations can provide prognostic information, including internal tandem duplications within the FLT3 gene, partial tandem duplication of the MLL gene, mislocalizing mutations of the NPM1 gene, mutations in the CEBPA and RAS genes, and increased expression of the BAALC and ERG genes. 5,6owever, these parameters and others such as patient age are only partially successful at capturing risk of relapse and patient outcomes following treatment.A growing body of evidence suggests that specific cancer cell subpopu-Context 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. ObjectiveTo identify an LSC gene expression signature and test its association with clinical outcomes in AML. Design, Setting, and PatientsRetrospective 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). Main Outcome MeasuresIdentification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSCspecific genes with overall, event-free, and relapse-free survival and with therapeutic response. ResultsExpression 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 PϽ.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). ConclusionHigh expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.