Abstract
Recent studies have significantly improved our understanding of the role microRNAs (miRNAs) play in regulating normal hematopoiesis. miRNAs are critical for maintaining hematopoietic stem cell function and the development of mature progeny. Thus, perhaps it is not surprising that miRNAs serve as oncogenes and tumor suppressors in hematologic malignancies arising from hematopoietic stem and progenitor cells, such as the myeloid disorders. A number of studies have extensively documented the widespread dysregulation of miRNA expression in human acute myeloid leukemia (AML), inspiring numerous explorations of the functional role of miRNAs in myeloid leukemogenesis. While these investigations have confirmed that a large number of miRNAs exhibit altered expression in AML, only a small fraction has been confirmed as functional mediators of AML development or maintenance. Herein, we summarize the miRNAs for which strong experimental evidence supports their functional roles in AML pathogenesis. We also discuss the implications of these studies on the development of miRNA-directed therapies in AML.
Highlights
Hematopoietic stem cells (HSCs) exhibit the unique ability to undergo self-renewal and to give rise to all cells of the hematopoietic system throughout the lifetime of an organism (Weissman, 2000; Kondo et al, 2003)
DIRECTIONS numerous miRNAs are dysregulated in acute myeloid leukemia (AML), only a few have been shown to play functional roles in myeloid leukemogenesis (Table 2)
It is worth mentioning that miRNAs may act in nonhematopoietic cell-intrinsic manners to promote leukemogenesis, as demonstrated by Raaijmakers et al (2010), who showed that deleting the miRNA processing enzyme, DICER1, in mouse osteoprogenitors induces myelodysplastic syndromes (MDS) which progresses to AML
Summary
Hematopoietic stem cells (HSCs) exhibit the unique ability to undergo self-renewal and to give rise to all cells of the hematopoietic system throughout the lifetime of an organism (Weissman, 2000; Kondo et al, 2003). The miR-125 family regulates self-renewal, both in HSCs as well as fetal MP and MEPs. The variance in hematopoietic phenotypes induced by miR-125 overexpression can be attributed, in large part, to the level of overexpression, with lower levels of miR-125 expression regulating hematopoietic differentiation and proliferation and leading to myeloid (and sometimes T-cell) expansion at the expense of B cells, while the highest levels induce the development of a MPN-like phenotype that progresses to AML (Table 1). The variance in hematopoietic phenotypes induced by miR-125 overexpression can be attributed, in large part, to the level of overexpression, with lower levels of miR-125 expression regulating hematopoietic differentiation and proliferation and leading to myeloid (and sometimes T-cell) expansion at the expense of B cells, while the highest levels induce the development of a MPN-like phenotype that progresses to AML (Table 1) The relevance of these studies to human disease is worth considering, as miR-125 is upregulated by no more than 90-fold in myeloid malignancies (Bousquet et al, 2008). MiR-146a AND NORMAL HEMATOPOIESIS In normal hematopoiesis, miR-146a is a negative regulator of megakaryopoiesis and granulocyte/macrophage differentiation
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