A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a ‘core enriched’ (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CEhigh) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CEhigh patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CElow patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CEhigh status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CEhigh patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.

Cancer Stem Cells

“…Instead two unipotent basal and luminal stem cells were identified. The same was described in prostate development (Liu et al 2011; Table 1 Tumor-initiating cell-related gene signature studies reporting prognostic signatures in independent patient data derived from bulk cells (Glinsky et al 2005;Phillips et al 2006;Liu et al 2007;Shipitsin et al 2007;Stevenson et al 2009;Gentles et al 2010;Eppert et al 2011;Merlos-Suarez et al 2011;Becker et al 2012;Liu et al 2012;Atkinson et al 2013;Metzeler et al 2013;Schwede et al 2013;Van den Broeck et al 2013;Peng et al 2014;Yin et al 2014;Pfefferle et al 2015;Yang et al 2015) Cancer Type Signature Source…”

An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers

“…However, AML patients whose cells are engraftment-capable have worse outcomes (Kennedy and colleagues; unpublished data; ref. 7), and thus are in greatest (5)(6)(7). For example, a functionally defined LSC-specific gene expression signature is highly prognostic in multiple independent AML cohorts (5,6), suggesting that common pathways that are operative within LSC-enriched (i.e., xenograft-initiating) cell fractions are linked to outcome in all patients.…”

“…7), and thus are in greatest (5)(6)(7). For example, a functionally defined LSC-specific gene expression signature is highly prognostic in multiple independent AML cohorts (5,6), suggesting that common pathways that are operative within LSC-enriched (i.e., xenograft-initiating) cell fractions are linked to outcome in all patients. This link also implies that, regardless of a patient's mutational spectrum and even when the subclonal composition of a xenograft does not reflect the dominant leukemic clone in a patient (28), the common stemness pathways that govern engrafting cells represent potentially relevant therapeutic targets.…”

“…Tumor heterogeneity is also not well modeled by (frequently nonorthotopic) injection of human cancer cell lines into mice, or even by engineered mouse models; the low variability and good reproducibility of the latter are actually disadvantageous for drug testing as they do not reflect intratumor and interpatient heterogeneity (3,4). Xenotransplantation of primary cancer cells is currently the best functional assay for both normal and malignant adult human stem cells, and in the context of human acute myeloid leukemia (AML) reads out clinically relevant properties of repopulating cells (5)(6)(7). Numerous previous studies have evaluated the efficacy of antileukemia drugs in the setting of xenotransplantation assays (8)(9)(10)(11)(12); however, the number of primary patient samples tested has generally been small, thus precluding biomarker development.…”

Bringing Leukemia Stem Cells into the Clinic

“…A 17-gene signature produced per-patient scores that were significantly correlated to overall survival in all cohorts tested in both univariate and multivariate analyses. These cohorts include patients with abnormal cytogenetics; thus, this new LSC signature will be more widely applicable than our originally published signature derived from 16 patient samples [9], which has been validated primarily in cytogenetically normal AML patient cohorts [10]. Once validated, this new LSC signature will be tested in a prospective clinical trial for its value in identifying patients at high risk of relapse who may benefit from intensified treatment.…”