Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice

Abstract

IntroductionHematopoiesis is a tightly regulated process of proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs) toward mature blood cells. Lineage commitment and differentiation of HSPCs are orchestrated by transcription factors that are expressed at specific developmental stages. For example, CCAAT/ Enhancer-Binding Protein-Alpha (C/EBPA) is a master regulatory transcription factor that is not expressed in hematopoietic stem cells (HSCs), but starts to be expressed in a small fraction of multipotent progenitor (MPP) cells and increases steeply during the transition from the common myeloid progenitor (CMP) toward the GMP. C/EBPA drives granulopoiesis by controlling the expression of myeloid-specific genes. 1-2 miRNAs belong to a class of small (approximately 22 nt) noncoding RNAs. The RNA-induced silencing complex-bound miRNAs bind to complementary sequences that are predominantly located in the 3Ј-untranslated regions of target mRNAs and regulate gene expression by transcript destabilization and inhibition of protein translation. 3 Recently, the function of miRNAs in myeloid cells has been investigated using mouse models. For example, miRs-17/20/93/106 promote progenitor cell expansion by targeting Sequestosome-1-regulated pathways. 4 In addition, miR-223 negatively regulates myeloid progenitor proliferation and fine-tunes granulocyte differentiation and activity. 5 In addition, miR-146a inhibits the activity of both myeloid and lymphoid cell lineages and plays key roles in the regulation of inflammation. 6 DICER1 is an evolutionarily conserved member of the RNase III family of endoribonucleases that is critical for processing of specific precursor hairpin sequences, the so-called pre-miRNAs, into miRNAs. 7 Genetic deletion of Dicer1 in mice results in early embryonic mortality due to depletion of the Oct-4-positive pluripotent embryonic stem cell pool at embryonic day 6-7 (E6-E7). 8 A floxed Dicer1 allele (Dicer1 fl ) has been generated that allows conditional deletion of Dicer1 in a cell type-and developmental stage-specific fashion. 9 Hematopoietic lineage-specific conditional deletion of Dicer1 has revealed the involvement of miRNAs in the survival, maturation, and homeostasis of peripheral T lymphocytes and in Ab diversity and survival of B lymphocytes. [10][11][12] In addition, conditional Dicer1 deletion in osteoprogenitors using mice that have Cre recombinase under the transcriptional control of the osterix promoter (Osx-GFP-Cre) results in myeloid dysplasia and acute myelogenous leukemia with acquired genetic abnormalities but intact Dicer1. 13 Mouse primary HSCs are impaired by Dicer1 loss and are unable to reconstitute hematopoiesis. 14 In addition, conditional deletion of Ars2, another gene required for miRNA biogenesis, in HSCs results in BM failure and increased apoptosis of hematopoietic cells in thymus and spleen. 15 Therefore, the overall contribution of miRNAs to myeloid-lineage specification remains elusive. To address this issue, we generated a myeloid-specif...

Dicer is selectively important for the earliest stages of erythroid development

“…Specific deletion of Dicer in myeloid progenitors, using Cebpa-Cre, does not result in impaired GMP formation. 19 The observed reduction of GMPs may therefore reflect that earlier, and possibly more efficient, Dicer depletion is able to reveal a role for miRs in myeloid lineage progression.…”

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

“…miRNA contributions to normal hematopoiesis have been described, and deletion of key miRNA processing enzymes in murine and human cells suggests that miRNA loss contributes to the cancer phenotype and aberrant differentiation in leukemia (19)(20)(21).…”

Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21–mediated tumor suppressor Pdcd4 repression

“…Although several miRNA candidates have been shown to modulate the onset of Notch1-driven T-ALL in mouse models, 8,10,11,13 it remains unclear whether miRNAs are essential for onset and/or maintenance of this disease. Here, we show that CD4-Cre-mediated LOF of Dicer1 BLOOD, 20 AUGUST 2015 x VOLUME 126, NUMBER 8…”

“…Using Dicer1 loss-offunction (LOF) studies, the global requirement for miRNA biogenesis in B-cell acute lymphoblastic leukemia (B-ALL), myelodysplastic syndrome, and acute myeloid leukemia (AML) was recently assessed. [7][8][9] It became clear that miRNA dependency varies widely between different types of leukemia. [7][8][9] Whereas the global requirement of miRNAs in T-cell acute lymphoblastic leukemia (T-ALL) remains elusive, various studies have been carried out identifying several miRNA candidates relevant to T-ALL onset.…”

“…[7][8][9] It became clear that miRNA dependency varies widely between different types of leukemia. [7][8][9] Whereas the global requirement of miRNAs in T-cell acute lymphoblastic leukemia (T-ALL) remains elusive, various studies have been carried out identifying several miRNA candidates relevant to T-ALL onset. [10][11][12][13][14] A comprehensive miRNA expression study using human T-ALL samples revealed that 5 highly abundantly expressed miRNAs function in a protumorigenic manner in a mouse model of Notch1-driven T-ALL.…”