Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

Abstract

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. 1,2 Recent 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. 5,6 However, 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.Objective To 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.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; ...

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

“…Since these LSC -particularly in their dormant stage -may survive treatment and give rise to subsequent relapse [19,[28][29][30][31][32][33][34][35][36][37][38][39]. The latter idea is supported by a recent study showing that a higher level of putative CD34 + /CD38 --LSC is associated with a worse prognosis [40].…”

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

“…Very recently, also Gentles et al 38 defined a leukemic stem cell gene expression signature and found this signature to be strongly associated with clinical outcome in AML. The LSC signature identified by Gentles et al was shown to be highly expressed not only in leukemic, but also in normal hematopoietic stem cells.…”

The epigenome of AML stem and progenitor cells

“…These were 28 stem cell specific genes and 20 progenitor cell specific genes. 25 Since we found that K4 was the most reliable marks of gene expression, we focused on loss and gain of K4 enrichment upon differentiation. In P10 AML cells, we found that 5 out of 28 (18%) stem cell-expressed genes had only K4 marks in stem cells that were lost in progenitor cells compared with only 1 out of 20 progenitor cell-expressed gene (5%) (Fig.…”

“…This was most striking for bivalent genes that decreased to less than half of those in stem cells only, K27 only, bivalent, and bi-negative. Using publicly available AML stem and progenitor expression patterns (accession number GSE24006), 25 we categorized genes depending on their expression into high, intermediate, and low in stem and progenitor cells, and correlated these with K4 and K27 peaks (Fig. 3A).…”