XLSX file - 54KB, Genes correlated with microRNA-126 expression in 163 AML patients show overlap with stem cell genes: Genes positively and negatively associated with miR-126 expression in 163 AML patients as published by (34). 854 genes were significantly correlated in a Spearman's rank correlation analysis with a significance threshold of univariate tests <0.001. Correlation coefficient, Parametric p-value and FDR are shown. Correlated genes were compared with the previously published HSC and LSC gene signatures of Eppert et al. (7). Genes that are associated with miR-126 and are also found in the LSC signature are shown in columns LSC-R FDR <0.05 and FDR <.0.01. Correlated genes that overlap with HSC signatures are shown under HSC-R <0.05. N/A, no overlap.
ARTICLE ABSTRACT
Despite high remission rates after therapy, 60% to 70% of patients with acute myeloid leukemia (AML) do not survive 5 years after their initial diagnosis. The main cause of treatment failures may be insufficient eradication of a subpopulation of leukemic stem-like cells (LSC), which are thought to be responsible for relapse by giving rise to more differentiated leukemic progenitors (LP). To address the need for therapeutic targets in LSCs, we compared microRNA (miRNA) expression patterns in highly enriched healthy CD34+CD38− hematopoietic stem cells (HSC), CD34+CD38− LSCs, and CD34+CD38+ LPs, all derived from the same patients' bone marrow (BM) specimens. In this manner, we identified multiple differentially expressed miRNAs, in particular miR-126, which was highly expressed in HSCs and increased in LSCs compared with LPs, consistent with a stem-like cell function. High miR-126 expression in AML was associated with poor survival, higher chance of relapse, and expression of genes present in LSC/HSC signatures. Notably, attenuating miR-126 expression in AML cells reduced in vitro cell growth by inducing apoptosis, but did not affect the survival of normal BM in which it instead enhanced expansion of HSCs. Furthermore, targeting miR-126 in LSCs and LPs reduced their clonogenic capacity and eliminated leukemic cells, again in the absence of similar inhibitory effects on normal BM cells. Our results define miR-126 as a therapeutic focus to specifically eradicate LSCs and improve AML outcome. Cancer Res; 74(7); 2094–105. ©2014 AACR.
