The role of microRNAs in hematopoietic stem cell and leukemic stem cell function

Abstract

Hematopoietic stem cells (HSCs) are defined by their ability to self-renew and reconstitute all elements of the hematopoietic system. Acute myeloid leukemia (AML) is thought to arise from, and be maintained by, leukemic stem cells (LSCs), which exhibit similar features to HSCs, including the abilities to self-renew and differentiate into non-self-renewing cells. Acquisition of stem-cell-like characteristics by the LSCs is likely mediated in part by molecular mechanisms that normally regulate HSC function. Thus, understanding the shared and unique aspects of the molecular regulation of these cell populations will be important to understanding the relationship between normal hematopoiesis and leukemogenesis. MicroRNAs (miRNAs) are small noncoding RNAs that act at the posttranscriptional level to regulate protein expression. Unfortunately, most investigations of the role of miRNAs in normal hematopoiesis have been restricted to studies of their effects on lineage commitment in progenitors and mature effector cell function, but not on HSCs. Recent studies have identified miRNAs that enhance HSC function, and an abundance of profiling studies using primary AML samples have identified dysregulated miRNAs that may target genes implicated in self-renewal (HOX genes, P53, and PTEN), thus providing a potential link between normal and malignant stem cells. While these studies as well as recent in vivo models of miRNA-induced leukemogenesis (e.g. miR-29a, miR-125b) suggest a role for miRNAs in the development of AML, future studies using serial transplantation of primary AML blasts, from both mouse models and primary human AML specimens, will be necessary to assess the roles of miRNAs in LSC biology.