Attenuation of microRNA-126 expression that drives CD34+38- stem/progenitor cells in acute myeloid leukemia leads to tumor eradication
Menée in vitro, cette étude suggère l'intérêt de cibler le micro-ARN 126 pour éradiquer les cellules souches leucémiques sans affecter les cellules normales de la moelle osseuse et, ainsi, améliorer le traitement d'une leucémie myéloïde aiguë
Despite high remission rates after therapy, 60-70% of acute myeloid leukemia (AML) patients do not survive five 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 LSC, we compared microRNA expression patterns in highly enriched healthy CD34+CD38- hematopoietic stem cells (HSC), CD34+CD38- LSC and CD34+CD38+ LP, all derived from the same patients' bone marrow specimens (BM). In this manner, we identified multiple differentially expressed microRNAs, in particular miR-126 which was highly expressed in HSC and increased in LSC compared to LP, 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 where it instead enhanced expansion of HSC. Furthermore, targeting miR-126 in LSC and LP 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 LSC and improve AML outcome.