MicroRNAs in Control of Stem Cells in Normal and Malignant Hematopoiesis

Abstract

Studies on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have helped to establish the paradigms of normal and cancer stem cell concepts. For both HSCs and LSCs, specific gene expression programs endowed by their epigenome functionally distinguish them from their differentiated progenies. MicroRNAs (miRNAs), as a class of small non-coding RNAs, act to control post-transcriptional gene expression. Research in the past decade has yielded exciting findings elucidating the roles of miRNAs in control of multiple facets of HSC and LSC biology. Here we review recent progresses on the functions of miRNAs in HSC emergence during development, HSC switch from a fetal/neonatal program to an adult program, HSC self-renewal and quiescence, HSC aging, HSC niche, and malignant stem cells. While multiple different miRNAs regulate a diverse array of targets, two common themes emerge in HSC and LSC biology: miRNA mediated regulation of epigenetic machinery and cell signaling pathways. In addition, we propose that miRNAs themselves behave like epigenetic regulators, as they possess key biochemical and biological properties that can provide both stability and alterability to the epigenetic program. Overall, the studies of miRNAs in stem cells in the hematologic contexts not only provide key understandings to post-transcriptional gene regulation mechanisms in HSCs and LSCs, but also will lend key insights for other stem cell fields.

miR-125b promotes MLL-AF9–driven murine acute myeloid leukemia involving a VEGFA-mediated non–cell-intrinsic mechanism

“…[4][5][6][7] Overexpression of miR-125a and miR-125b is often observed in myeloid and lymphoid malignancy specimens. 3,[8][9][10][11][12][13][14] miR-125b has been estimated to be overexpressed in ;15% to 25% of human acute myeloid leukemias (AMLs) 3,12,[15][16][17] (supplemental Figure 1, available on the Blood Web site; Figure 7). Mechanisms of such deregulation are likely diverse, including rare translocations, chromosomal amplification, [8][9][10]15,18 and transcriptional regulation.…”

The 14q32.31DLK1-DIO3 MIR300 tumor suppressorpromotes leukemogenesis by inducing cancer stem cell quiescence and inhibiting NK cell anti-cancer immunity

“…miR-29, miR-125, miR-126, let-7) or survival of quiescent cells (e.g. mir-16 family) have been associated with CSC expansion and maintenance 4 . For example, miR-126, which targets CDK3, inhibits qLSC re-entry into cycle but does not induce quiescence and, importantly, it is not acting as a tumor suppressor in AML/CML LSCs 9,10 .…”

“…For example, miR-126, which targets CDK3, inhibits qLSC re-entry into cycle but does not induce quiescence and, importantly, it is not acting as a tumor suppressor in AML/CML LSCs 9,10 . Less clear and controversial is the role of miR-221/222/223 in CSC quiescence since their expression is regulated by MSCs in a tumor-and cell type-specific manner but also increases in response to mitogenic stimuli to induce CDK4/CCND1-dependent cell cycle re-entry 4,11 .…”

“…Gain or loss of miRNA expression/function is a feature of cancer cells including CSCs 4,5 in which they may function as oncogenes or tumor suppressors influencing CSC's function, tumor growth and innate anti-cancer immunity 6,7 . Several miRNAs have been associated with CSC expansion and maintenance 4 and PP2A inactivation 8 ; however, a clear causal link between expression of specific miRNAs, persistence of the drug-resistant quiescent CSCs and PP2A loss-of-function is still missing.…”

“…Several miRNAs have been associated with CSC expansion and maintenance 4 and PP2A inactivation 8 ; however, a clear causal link between expression of specific miRNAs, persistence of the drug-resistant quiescent CSCs and PP2A loss-of-function is still missing. Furthermore, these miRNAs mostly act as regulators of CSC survival, maintenance into dormancy and cell cycle re-entry but it is unclear whether any of them directly promotes CSC cell cycle exit 4,[9][10][11] .…”