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.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous disorder that includes many entities with diverse genetic abnormalities and clinical features [1]
Because not every patient with AML has detectable hematopoietic stem cell (HSC) and/ or leukemic stem cells" (LSC), we first analyzed a series of AML bone marrow (BM) samples (n > 50) for presence of both leukemic and normal CD34þCD38À cells by using the aldehyde dehydrogenase (ALDH) activity assay in combination with presence or absence of an immunophenotypical leukemia-associated marker expressed on the particular AML
Our study represents the first effort to simultaneously compare miRNA expression profiles of all these fractions from the same AML BM, which takes into account the influence of the AML microenvironment on the expression profiles
Summary
Acute myeloid leukemia (AML) is a heterogeneous disorder that includes many entities with diverse genetic abnormalities and clinical features [1]. A minority of cells within AML is responsible for sustaining and maintaining the leukemia [2]. These leukemia-maintaining cells have many features in common with somatic normal stem cells and can self-renew and differentiate, which have given them the name "leukemic stem cells" (LSC). LSC frequency at diagnosis as well as after treatment and LSC and hematopoietic stem cell (HSC) gene expression signatures have been linked to AML outcome [3, 6, 7]. Eradication of persistent LSCs will improve long-term AML outcome
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