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MicroRNAs (miRNAs) belong to an abundant class of highly conserved small (22nt) non-coding RNAs. MiRNA profiling studies indicate that their expression is highly cell type-dependent. DICER1 is an essential RNase III endoribonuclease for miRNA processing. Hematopoietic cell type- and developmental stage-specific Dicer1 deletion models show that miRNAs are essential regulators of cellular survival, differentiation and function. For instance, miRNA deficiency in hematopoietic stem cells and progenitors of different origins results in decreased cell survival, dramatic developmental aberrations or dysfunctions in mice. We recently found that homozygous Dicer1 deletion in myeloid-committed progenitors results in an aberrant expression of stem cell genes and induces a regained self-renewal capacity. Moreover, Dicer1 deletion causes a block in macrophage development and myeloid dysplasia, a cellular condition that may be considered as a preleukemic state. However, Dicer1-null cells do not develop leukemia in mice, indicating that depletion of miRNAs is not enough for tumorigenesis. Surprisingly, we found that heterozygous Dicer1 deletion in myeloid-committed progenitors, but not Dicer1 knockout, collaborates with p53 deletion in leukemic progression and results in various types of leukemia. Our data indicate that Dicer1 is a haploinsufficient tumorsuppressor in hematopoietic neoplasms, which is consistent with the observed downregulation of miRNA expression in human leukemia samples. Here, we review the various hematopoietic specific Dicer1 deletion mouse models and the phenotypes observed within the different hematopoietic lineages and cell developmental stages. Finally, we discuss the role for DICER1 in mouse and human malignant hematopoiesis.

Purpose of Review: Recent data show that microRNAs play critical roles in the regulation of the developmental process of hematopoietic stem and progenitor cells toward mature myeloid cells. The main focus of the article is the function of some evolutionary conserved microRNAs that are abundantly expressed and tightly regulated during myelopoiesis., Recent Findings: Global microRNA depletion studies in hematopoietic stem cells have shown the importance of microRNA-controlled pathways for hematopoiesis. Recent insights from genetic mouse models and overexpression or deletion of microRNAs in developmental cell intermediates demonstrate strong evidence for evolutionary conserved microRNA-regulated pathways involved in tight control of cellular processes such as proliferation, differentiation and apoptosis at different stages of blood cell development. It is becoming evident that the myeloid transcription factor PU.1 regulates the expression of critical microRNAs including miR-17∼92 and miR-146a during myelopoiesis. Furthermore, there is evidence for the contribution of aberrant miR-125 activities in hematopoietic disorders including myeloid leukemia., Summary: Despite the large number of articles describing differential microRNA expression during hematopoiesis, microRNA functions and their downstream pathways in myeloid lineage decisions and leukemia are only recently emerging. Here we discuss new findings concerning PU.1-controlled microRNAs and miR-125-regulated networks in normal and malignant myelopoiesis.