High LSC scores associated with adverse outcomes in AML patients

JAMA and Archives JournalsDec 21 2010

In an examination of leukemic stem cells (LSC), researchers have found that patients with acute myeloid leukemia who had higher activity of certain LSC genes had worse overall, event-free and relapse-free survival, according to a study in the December 22/29 issue of JAMA.

"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," according to background information in the article. "A major implication of this cancer stem cell model is that the LSCs must be eliminated to eradicate the cancer and cure the patient. While AML was the first human malignancy for which this model gained experimental support, its clinical significance has yet to be fully established."

Andrew J. Gentles, Ph.D., of Stanford University, Palo Alto, Calif., and colleagues examined gene expression (activity) profiles of LSC-enriched (higher concentration) subpopulations from primary AML and normal patient samples. These samples were obtained at a U.S. medical center between April 2005 and July 2007. Other data sets of profiles of AML tumors from 4 independent groups (n = 1,047) also were evaluated.

The researchers found that 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 primary AML tumor samples was associated with clinical outcomes in the 4 independent patient groups. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes (set of chromosomes of a cell) or chromosomal abnormalities.

"The absolute risk of death by 3 years was 57 percent for the low LSC score group compared with 78 percent for the high LSC score group. 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 percent in the low LSC score group vs. 81 percent in the high LSC score group," the researchers write.

The LSC score was also associated with primary response to induction chemotherapy, because high LSC scores strongly correlated with lower remission rates.

"In this study, we show that a gene expression score associated with the LSC-enriched subpopulation is an independent prognostic factor in AML, with high LSC score associated with adverse outcomes in multiple independent cohorts. - If prospectively validated, the described LSC score may be incorporated into routine clinical practice for predicting prognosis in patients with AML and used in clinical trials incorporating risk-based stratification or randomization strategies."

The researchers add that this study is the first to directly define a signature (a group of genes whose level of activity distinguishes one cell type from another) of enriched AML-initiating cells and to relate this signature to expression profiles of diagnostic specimens, allowing a link to corresponding clinical and pathological features of patients. "Ultimately, this model has major implications for cancer therapy, most notably that in order to achieve cure, the cancer stem cells must be eliminated. To accomplish this in AML, novel therapies targeting LSC must be developed."